Pediatric Infectious Disease Newsletter

May 2010  

Norovirus on a Plane!
We've all heard about norovirus outbreaks on cruise ships, and long flights, but now it appears you can get norovirus in the time it takes to travel from Logan to O'Hare! In October of 2008 six members of a group of tourists traveling from Boston back home to Los Angeles fell ill with norovirus gastroenteritis en route. The plane was diverted to Chicago after a flight time of three hours so that the ill passengers could disembark the plane. Despite the short duration of contact with the ill passengers, seven other passengers not associated with the tour group fell ill with symptoms of norovirus within 2-4 days after being on the airplane. Risk factors for transmission were: sitting near a tour member and sitting in an aisle seat. Presumably, these risk factors may have been due to a higher incidence of person-to-person or environmental spread.

Norovirus is particularly problematic due to its high attack rate, its ease of spread (person to person, contact with fomites, aerosolization of viral particles) and its resistance to common disinfectants. (Alcohol-based hand sanitizer is ineffective.)

Kirking, HL et al. Clin Infect Dis 2010: 50. 1216-21
How to Clean Noroviruses
Noroviruses cause gastroenteritis and are associated with outbreaks in crowded situations, such as cruise ships. We have known that alcohol-based hand sanitizers are less effective than handwashing because the virus lacks a lipid envelope. A new study confirmed that noroviruses inoculated onto the fingers of test subjects were not removed by alcohol hand sanitizers, but they were removed by washing with a triclosan-containing (antibacterial) soap and even by plain water. Plain water was as effective as soap with water. Friction is the important element for removing these viruses.

Appl Environ Microbiol 2010;76:394
Take Part in Our Vaccine Survey

A Message from David Berman, D.O.

Pediatric Infectious Disease Program
All Children's Specialty Physician

David Berman, D.O., FAAP
All physicians are encouraged to complete the brief survey regardless of your opinion regarding childhood vaccination. If enough responses are received, the anonymous results will be presented at the Annual Suncoast Pediatric Conference (Sarasota, Florida) in June 2010. Conference registration is available online.

Thank you for your participation.
Rabies in Solid Organ Transplant Patients
Transmission of rabies via solid organ transplantation is a rare occurrence. Transmission of rabies via corneal transplant has occurred sporadically, but the first reported occurrence through solid organ transplantation was in the United States in 2004. This event involved four transplant recipients who ultimately died of rabies infection transmitted to them from a single organ donor - a young man whose rabies infection went undiagnosed at the time of his death from presumed stroke. Nine months later a similar event occurred in Germany when a 26-year-old female organ donor (who presented with symptoms of encephalopathy and later died of multi-system organ failure) provided two corneas, one liver, one lung, one kidney and one kidney-pancreas to six patients. The donor's rabies infection also went undetected in this case until after her death.

Unlike the event in the US, three out of six German transplant recipients survived, uninfected (at least as of this time). The two patients who received corneal transplants had their grafts removed and remained asymptomatic (presumably, viral load in the corneas was not sufficient enough to cause infection). Three of the remaining four patients, however, died even after rabies prophylaxis was initiated. The sole survivor was a 26-year-old male who received the infected liver. Interestingly, upon further history, the young man's mother recalled that her son had received post-exposure rabies vaccine as a child (over 20 years prior to getting his liver transplant!). Virus-neutralizing antibody to rabies was subsequently detected in a sample of this patient's archived, pre-transplant blood!

This interesting event highlights a couple important take home messages:
  1. Rabies vaccine is remarkably effective
  2. A good clinical history makes ALL the difference!! Not only is it important to have an astute mom, but it was sad that this history was not available on the young female organ donor at the time of her death: She had been traveling in India a few months prior to her death and had been bitten by a stray dog while there. She did not seek medical attention for her injury, nor did she inform anyone about the attack. The event was recalled by a fellow traveler who did not know of her illness or death until months after the fact.
Maier, T et al. Clin Infect Dis 2010:50 (15 April) 1112-1119
Leptospirosis in Florida Adventure Racers
Leptospirosis is a diagnosis we seldom make, but it is probably more prevalent that we know! Leptospirosis is a bacterial zoonosis widely prevalent throughout the world. Illness is caused by the spirochete genus Leptospira. Over 200 serovars have been described. Human infection is acquired through direct contact with infected animals and their urine, or through environments contaminated with animal waste. Up to 90% of leptospiral infections are sub-clinical or mildly symptomatic. Five to 10% are more severe with the most common presentation being severe, acute febrile illness with headache, severe myalgia, eye pain, conjunctival suffusion, jaundice, dark urine, hepatitis, rash and unusual bleeding. Death can occur from multi-organ system failure. Doxycycline is the drug of choice for treatment.

In 2005, an outbreak of Leptospirosis occurred in 44 of 192 (23%) adventure race participants competing in a race at Hillsborough River State Park near Tampa. The race involved paddling, cycling, trekking and orienteering. During the race, participants had prolonged exposure to surface water from streams, creeks and swamps.  About two weeks before the race, Hurricane Wilma had hit the area, causing flooding of surrounding areas-which were home to a variety of wild animals and some livestock. Epidemiological investigation found that the following risk factors increased risk of infection: swallowing river or swamp water, being submerged in water, and eating wet food.

In any patient with symptoms of leptospirosis, a good history is important. Ask not only about animal exposures, but also about exposure to water sources.

Stern, EJ et al. Clin Infect Dis 2010: 50 (15 March) 843-49
Seroprevalence of HSV Types 1 and 2
Herpes simplex virus (HSV) type 1 and 2 are common infections throughout the world. They are responsible for a vast array of clinical symptoms ranging from mild disease--e.g. herpes labialis (the common "cold sore") to very severe diseases such as neonatal disseminated HSV. HSV-2 is the most common--though by no means the exclusive--cause of genital herpes, while HSV-1 is usually (though, not exclusively) transmitted via non-sexual contacts.

When an individual is infected with HSV 1 or 2, it never really goes away! Like all herpes infections, when they are not causing active disease, HSV 1 and 2 find a home for themselves in their host's dorsal root ganglia -where they lie in their latent state. Additionally, once one is infected with HSV 1 or 2, they produce antibodies which persist for life.

A 2006 study looked at the seroprevalence of HSV 1 and 2 in the general healthy U.S. population. Using banked sera collected as part of the US National Health and Nutrition Examination Survey (NHANES) study, they tested samples from 11,508 persons ages 14-49 years of age for HSV-1 and HSV-2 specific antibody (IgG). They discovered that the overall age-adjusted prevalence of HSV-1 was 57.7%. The seroprevalence of HSV-2 was 17%. Both the prevalence of HSV-1 and 2 varied by age. As expected, the oldest age group studied (40-49 yr) had higher seroprevalence of both HSV-1 (39% vs 65%) and HSV-2  (1.6% vs. 26.4%) than the youngest age group studied (14-19 yr olds).

A similar study, however, further defined the seroprevalence of HSV-1 in an even younger population using NHANES data from stored samples of sera from 6-13 year olds. They similarly found a high prevalence (31.1%) of HSV-1 seropositivity in this age group.

Take home message? HSV is a common disease! Both HSV 1 and 2 can cause identical symptoms. Once one is infected with HSV, expect that person's HSV IgG to remain positive for life! This does not mean they are actively shedding the virus, nor does it mean they will have symptomatic disease. Also, it is generally not possible to determine the time of acquisition of HSV by IgG measurement alone. In order to make a diagnosis of active HSV disease, tests to look for actual virus itself (not just antibody) are needed. Viral culture from an HSV lesion on the skin is quite sensitive as is HSV PCR from the blood and spinal fluid. (Note: HSV culture from the blood and spinal fluid is NOT at all sensitive, and in most cases should not be ordered!) One last reminder: measurement of specific IgG for ANY virus on a neonate is more likely to represent maternal than infant immune status, as IgG crosses the placenta.

Xu, F et al. JAMA August 23/30 2006, Vol 296, No. 8
Xu, F et al. J Pediatr , October 2007, p 374-77
Imported Marburg Virus in Colorado
The MMWR recently reported a case of Marburg virus in a returned 44-year-old traveler from Uganda. The patient's course consisted of hepatitis, renal failure, pancytopenia, myositis, coagulopathy, pancreatitis and encephalitis. Serological testing for leptospirosis, viral hepatitis, malaria, arboviral infection, acute schistosomiasis, rickettsial infection, and viral hemorrhagic fevers including Ebola and Marburg hemorrhagic fever were negative. Fortunately, the patient survived.

Her condition was not diagnosed until months later. Six months after her recovery, the patient learned that a fellow Dutch traveler who had been to the same cave she visited while in Uganda (Python Cave) had died of Marburg hemorrhagic fever. Her blood was tested again (six months later) for anti-Marburg IgG and was positive. Archived blood samples from the patient at the time of her illness were then tested for Marburg virus by PCR, and were positive.

This was the first report of imported filovirus (Marburg, Ebola) infection in the United States. The reservoir for these viruses is thought to be the fruit bat, and historically, many human cases have been linked to exploring caves. Contact with excreta of bats is thought to be the mode of spread. Travelers to endemic areas should be warned to avoid caves or mines inhabited by bats. Clinicians should have a high index of suspicion for viral hemorrhagic fever in patients presenting in multi-system organ failure after return from endemic areas. Suspicious cases should be reported to local health departments immediately.

MMWR 2009; 58 1377-80
Leggiadro, R. Ped Infect Dis J May 2009 p. 400
What's on the Horizon for RSV?
Respiratory Syncytial virus (RSV) is the leading cause of pediatric viral respiratory tract infection, causing an estimated ~160,000 deaths per year worldwide. It is also the second leading cause of viral death in the elderly. Despite the enormity of morbidity and mortality attributed to RSV, only 2 FDA approved drugs are available for this disease. The RSV monoclonal antibody, palivizumab (Synagis) is indicated only for prevention of RSV disease in high risk infants (those born prematurely, and those with cyanotic heart disease or lung disease). The only drug approved for treatment of RSV disease is ribavirin, though it may provide only limited benefit with significant potential for toxicity.

New drug candidates on the horizon for the treatment and prevention of RSV include:

New polyclonal antibody preparations: Much like the discontinued RSV-hyperimmune globulin (Respigam), a new product (RI-001, ADMA Biologicals) is in phase 2 clinical trials now. This product is derived from pooled healthy donors and would contain polyclonal antibodies to RSV. Potential advantages over the monoclonal antibody products would be: multiple antibodies targeting various viral epitopes and potential cross protection against other respiratory viruses and mutated RSV viruses.

New, higher affinity monoclonal RSV antibody products: Motavizumab (MedImmune) is, much like palivizumab, a monoclonal antibody to the RSV F surface glycoprotein. Motavizumab, however, has ~70-fold higher affinity to the F surface protein and 20-fold greater viral neutralizing capacity than does palivizumab. Recent phase 3 non-inferiority trials demonstrated 26% fewer RSV admissions and 50% reduction in RSV associated lower respiratory tract infection when compared to palivizumab. Additionally, this drug may also be able to more effectively reduce viral load of RSV in already infected patients.

New anti-virals for treatment of RSV: An anti-sense RNA drug (ALN-RSV01) (Alnylam Pharma) has just completed phase 2 trials and showed 38% reduction in RSV infection in adult drug recipients. This compound works by inhibiting viral protein synthesis. Several other drugs include viral fusion inhibitors and other small molecule compounds designed to bind specific RSV epitopes.

Active Vaccines: Current vaccine strategies against RSV are primarily aimed at developing a live, cold adapted vaccine (much like the Flu-Mist vaccine) for young infants (under 6 months of age). The reason for this strategy is multifactorial and includes creating a vaccine which will: induce mucosal as well as systemic immunity, be delivered in such a way (intranasally) which will hopefully escape neutralizing maternal antibody to a large extent, and provide broader protection against drifted strains. Most importantly, live vaccines have not been associated with enhancing viral disease (this was the problem with the RSV inactivated vaccine produced in the 1960s).

Empey, et al. Clin Infect Dis 2010:50 1258-67
How Long is a Person with 2009 novel H1N1 influenza A Contagious?
In a study done at the University of Quebec, 43 people who initially tested PCR-positive for novel H1N1 flu were retested at day 8 after the onset of symptoms and 16 of those people still positive on day 8 were retested again on day 11. They found that 74% of the 43 patients who tested positive for flu were still positive by PCR on day 8 and 19% were culture positive (meaning, they still had replicating virus) for flu. On day 11, 88% of those patients positive on day 8 were still PCR positive by day 11, but none were culture positive.

Most patients (95%), by day 8 were fever free for >24h. This study calls into question whether the policy of self-isolation for "24 hours after fever abates" is effective in preventing transmission of influenza. For the general population, a period of at least a week might be more effective. However, for those with exposure to more vulnerable people (infants, elderly, immunocompromised) longer periods of isolation may be warranted.

De Serres, G, et al. Emerg Infect Dis. 16(5) May 2010
Invasive S. pyogenes infection
The media is generally very focused on CA-MRSA infections.  We frequently underestimate the severity of other community-acquired infections like S. pyogenes.

We recently had four children hospitalized during the same time period with invasive S. pyogenes infection. Two patients had documented bacteremia, osteomyelitis, and cellulitis. The third patient had osteomyelitis and a recent history of pharyngitis with multiple household contacts with S. pyogenes.  The last patient had otomastoiditis with venous sinus thrombosis.  Reviewing our hospitalization data from the last three years, there has not been any increasing trend in invasive disease.

The Active Bacterial Core Surveillance of the Centers for Disease Control and Prevention is a surveillance system that covers nine states representing 31,143,540 persons.  The rate of invasive disease in 2008 (cellulitis, necrotizing fasciitis, pneumonia, bacteremia, and toxic shock) was 3.9/100,000 with the highest rate among adults >=65 years and children <1 year of age. The rate of death from invasive disease was 0.5/100,000.  In 2008, two cases of invasive S. pyogenes occurred in patients with varicella infection with one death. These were adult patients.

Other outbreaks have been described in the literature with common invasive clones among school-aged children.  In 1997, a report in JAMA described an invasive clone in adjacent counties in southeastern Minnesota. Using pulse-field gel electrophoresis, investigators were able to identify a common clone associated with an outbreak of invasive disease in their community. This clone had virulence factors (streptococcal superantigen and pyrogenic exotoxin A). Case-fatality rate was high in those that developed toxic shock. This same clone was also found among pharyngeal carriers.  Children in the outbreak area were more likely to carry the invasive S. pyogenes clone compared to children living outside the outbreak area

JAMA 1997; 277 (1):38-43
CDC.2009. ABC Report, Emerging Infections Program Network, Group A Streptococcus 2008
Q Fever Alert
CDC Health Advisory Alert

Healthcare providers in the United States should consider Q fever in the differential diagnosis of persons with febrile illness, pneumonia or hepatitis who have recently been in Iraq or the Netherlands due to endemic transmission in those areas.

Q fever is a zoonotic disease with both acute and chronic phases caused by the pathogen Coxiella burnetii.  The primary mode of transmission to humans is inhalation of aerosols or dust contaminated by infected animals, most commonly cattle, sheep or goats. Direct animal contact is not required for transmission to occur as the organism may be spread by dust or wind. Infections via ingestion of contaminated dairy products and human-to-human transmission via sexual contact have rarely been reported. Q fever does occur in the United States, but fewer than 200 cases are reported annually.
Although asymptomatic infections may occur, an unexplained febrile illness, sometimes accompanied by pneumonia and/or hepatitis, is the most common clinical presentation. Illness onset typically occurs within 2-3 weeks after exposure. The mortality rate for acute Q fever is low (1-2%), and the majority of persons with mild illness recover spontaneously within a few weeks although antibiotic treatment will shorten the duration of illness and lessen the risk of complications. Chronic Q fever is uncommon (<1% of acutely infected patients) but may cause endocarditis. Patients with pre-existing heart valve disorders, pregnant women, and immunosuppressed persons are at increased risk for developing chronic Q fever. A Q fever vaccine is not commercially available in the United States and antibiotic prophylaxis is not recommended. Probable and confirmed cases should be reported to their local or state health department.
Physicians seeing a patient - particularly military personnel or a civilian contractor - who has an illness consistent with Q fever and who has traveled to Iraq or the Netherlands in the 30 days prior to illness onset should perform appropriate laboratory testing. Serologic testing should be requested for IgG and IgM antibodies against C. burnetii Phase I and II antigen using indirect immunofluorescence assay (IFA). PCR assays may be conducted on whole blood samples in the early stages of illness and prior to initiation of antibiotic therapy.
Serologic evidence of a fourfold rise in IgG Phase II antibody by indirect immunofluorescence assay (IFA) between paired sera taken 2-4 weeks apart is the gold standard for diagnosis of acute infection. A single high serum Phase II IgG titer by IFA (≥ 1:128) is considered evidence of probable infection. IgM testing alone should not be used for serodiagnosis as false positives may occur. Treatment should not be delayed while awaiting laboratory results. Doxycycline (100mg twice a day for 2-3 weeks) is the treatment of choice for acute Q fever.

CDC Health Advisory, 5/12/2010
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In This Issue
Norovirus on a Plane!
How to Clean Noroviruses
Take Part in Our Vaccine Survey
Rabies in Solid Organ Transplant Patients
Leptospirosis in Florida Adventure Racers
Seroprevalence of HSV Types 1 and 2
Imported Marburg Virus in Colorado
What's on the Horizon for RSV?
How Long is a Person with 2009 novel H1N1 influenza A Contagious?
Invasive S. pyogenes infection
Q Fever Alert
Infectious Disease Newsletter Feedback
Opportunity for Current Vaccine Information
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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