Pediatric Infectious Disease Newsletter
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November 2009  

Update on Influenza A (H1N1) 2009 Monovalent Vaccines
On September 15, 2009, four influenza vaccine manufacturers received approval from the Food and Drug Administration for use of influenza A (H1N1) 2009 monovalent influenza vaccines in the prevention of influenza caused by the 2009 pandemic influenza A (H1N1) virus.* Both live, attenuated and inactivated influenza A (H1N1) 2009 monovalent vaccine formulations are available; each contains the strain A/California/7/2009(H1N1).

None of the approved influenza A 2009 (H1N1) monovalent vaccines or seasonal influenza vaccines in the United States contains adjuvants.

The approved age groups for use of inactivated influenza A (H1N1) monovalent influenza vaccines differ by manufacturer. Three manufacturers that produce inactivated vaccines approved for prevention of seasonal influenza also produce formulations of influenza A (H1N1) 2009 monovalent influenza vaccines. Three vaccines available for children are the:

  1. Inactivated vaccine produced by Novartis Vaccines and Diagnostics Limited which is approved for persons aged ≥ 4 years;
  2. Inactivated vaccine produced by Sanofi Pasteur, Inc. which is approved for persons aged ≥ 6 months
  3. Live attenuated influenza vaccine (LAIV) manufactured by MedImmune LLC is approved for persons aged 2-49 years.  The 2009 (H1N1) monovalent LAIV has the same age range for use as the seasonal LAIV and should not be used to vaccinate children aged < 2 years, adults aged > 49 years, pregnant women, persons with underlying medical conditions that confer a higher risk for influenza complications, or children aged < 5 years old with one or more episodes of wheezing in the past year.
 
Influenza A (H1N1) 2009 monovalent vaccine approvals were made on the basis of standards developed for vaccine strain changes for seasonal influenza vaccines, adherence to manufacturing processes, product quality testing, and lot release procedures developed for seasonal vaccines.

The age groups, precautions, and contraindications approved for the influenza A (H1N1) 2009 monovalent vaccine are identical to those approved for seasonal vaccines.

All influenza vaccines available in the United States for the 2009-10 influenza season are produced using embryonated hen's eggs and contain residual egg protein.

Preliminary data indicate that the immunogenicity and safety of these vaccines are similar to those of seasonal influenza vaccines. The National Institute of Allergy and Infectious Diseases (NIAID) reported preliminary results of a study among children aged 6 months-18 years. Among children aged 6-35 months, 3-9 years, and 10-17 years immunized with a 15 μg inactivated influenza A 2009 (H1N1) monovalent vaccine (Sanofi Pasteur, Inc., Swiftwater, PA), 25%, 36% and 76%, respectively, developed antibody titers of 1:40 or more (hemagglutination-inhibition assay) after a single dose of vaccine. Immunogenicity and safety study results similar to those observed for seasonal vaccines also have been reported by the other manufacturers (MedImmune LLC, Gaithersburg, MD and Novartis Vaccines and Diagnostics, Limited, Liverpool, UK, unpublished data, 2009).

Influenza A (H1N1) 2009 monovalent vaccines will be available in many areas by mid-October. Vaccines against seasonal influenza are available now, and immunization programs and providers should begin or continue administering seasonal influenza vaccines as recommended.  Additional data from clinical trials will be available over the coming weeks, and immunization providers should periodically look for updates on use of influenza A (2009).

CDC's Advisory Committee on Immunization Practices has made recommendations previously for which persons should be the initial targets for immunization with influenza A (H1N1) 2009 monovalent vaccines and has issued guidelines on decisions for expansion of vaccination efforts to other population groups. Children aged 6 months-9 years receiving influenza A (H1N1) 2009 monovalent vaccines should receive 2 doses, with doses separated by approximately 4 weeks; persons aged ≥ 10 years should receive 1 dose.

Additional information on influenza A (H1N1) 2009 monovalent vaccines are available on the CDC website.
 
MMWR. October 9, 2009 / 58(39);1100-1101
Novel H1N1 2009 Influenza Question
One of the many recent questions we have received about the current influenza pandemic is, "Should patients who had confirmed H1N1 influenza be given the monovalent H1N1 flu vaccine?" Unfortunately, the recently published CDC recommendations do not address this question (MMWR 2009;58:1-8). However, we can look at the CDC data for each month this summer to determine the probability that a patient who tested positive for influenza A had novel H1N1 flu. For the months of May through August, novel H1N1 comprised 89%, 94%, 94%, and 95% of all flu isolates tested at the CDC. For the week of September 19, it was 98%. Therefore, there's a good probability that patients who tested positive for influenza A during these months already have immunity. Patients who were not tested or patients who have risk factors for severe disease probably should still be immunized with the novel H1N1 vaccine, in case they were one of the few infected with a seasonal flu strain.
Florida Flu Hotline
On October 1, 2009, the Florida Poison Information Center-Tampa, one of the three regional poison control centers in Florida, activated a new call center. The center serves the Florida Department of Health to manage calls from health care providers for information from the Department of Health about the H1N1 Influenza and vaccinations against influenza.  Health care providers can ask questions and receive information about the H1N1 and seasonal influenza viruses, testing for influenza, vaccine availability and administration, antiviral administration, indications and contraindications, care for high- risk patients, reporting requirements, and vaccine safety.  Once vaccine becomes available, providers can report adverse reactions to the Poison Centers by calling the Flu Hotline number.

Health care providers with questions about the flu or vaccines can call the hotline for assistance by dialing 1 (877) 352 - 3581 and selecting option 2. The Flu hotline is currently operated between 8:00 AM and 8:00 PM.
2009 H1N1 Flu Situation Update
The CDC website provides current information on the US Seasonal Influenza. Is includes a Weekly Report (Flu View) and the Weekly US Map.
Nothing to Fear but the Flu Itself (New York Times)
This title references an article written by Paul Offit, MD. A version of this article appeared in print on October 12, 2009, on page A23 of the New York edition.
 
Opinion Section of the NY Times by Paul Offit, M.D.
 
Human Parechovirus
A newly recognized genus of virus closely related to the more familiar enteroviruses has been discovered. Parechovirus, in the family Picornaviridae. Parechovirus 1 and 2, initially classified as echoviruses 22 and 23 are now reclassified. To date, there are 8 known parechovirus serotypes. Parechoviruses appear to cause diseases similar if not identical to enteroviruses. They can cause the familiar clinical picture of respiratory, gastrointestinal and central nervous system infections. They can also cause severe sepsis syndrome, encephalitis and mycocarditis especially in neonates. Human parechoviruses (HPeVs) have been detected at lower incidence than enteroviruses. Of 155 specimens examined over an 8 year period, in a Netherlands lab, the breakdown of serotypes showed a predominance of HpeV 3 and 1 at 57% and 35% respectively. HpeV 5 accounted for 5%, HpeV 2, 1.3% and HpeV 4 (0.8%). HpeV 1 was primarily associated with mild GI and respiratory disease, though more severe cases including cases of mycocarditis and encephalitis were seen. HpeV 3 was found to cause neonatal sepsis as well as transient paralysis. The rest of the HpeV serotypes are more typically associated with mild GI disease. A serum PCR is available from the CDC for detection of these viruses. Routine, commercially available PCRs for enteroviruses will NOT pick up parechoviruses. No antiviral medication is known to be effective in their treatment.
Levorson, RE et al PIDJ Vol 28(9) 831-32.
Kawasaki Disease: Clinical Pearls
From a recent presentation at ACH:
  1. A positive throat culture does not rule it out.
  2. Treat with intravenous immunoglobulin (IVIG) 2 gm/kg no more than 2 times.
  3. Use high-dose steroids if 2 doses of IVIG fail. Use methylprednisone 30 mg/kg daily for 1-3 days.
  4. A normal echocardiogram at 6 weeks predicts a normal echo at 6 months.
  5. Bilateral conjunctival injection occurs simultaneously.
  6. Infants are more likely to develop coronary aneurysms.
  7. Convert from high-dose to low-dose aspirin when symptoms resolve.
Refer to the treatment guidelines at Circulation 2004:110:2747-71.
Are Steroids Safe for Kawasaki Disease?
Many of us learned that steroids increased the incidence of coronary artery disease in patients with Kawasaki disease based on a 1979 study that did not give details on patient characteristics (Kato H, et al. Pediatrics 1979;63:175-9). Since then, multiple studies have suggested possible benefits of steroids in these patients. A 2005 meta-analysis of 8 studies with 862 children showed a significantly lower rate of coronary artery aneurysms (CAA) when steroids were used with IVIG compared to IVIG alone (Wooditch AC, et al. Pediatrics 2005;116:989-95). A more recent study suggested that steroids with IVIG offered a shorter duration of fever, faster improvement of the C-reactive protein, fewer treatment failures, and a trend toward fewer CAA at 1 month (Inoue Y, et al. J Pediatr 2006;149:336-41). However, a more recent 2007 study showed no benefit of steroids on CAA size, number of days in the hospital, number of days of fever, or rates of IVIG retreatment. Nevertheless, there was a suggestion of possible benefit of initial treatment with steroids for patients who did require a second dose of IVIG.

Now, a recent retrospective review suggests that initial treatment with IVIG and steroids was associated with improved clinical and coronary outcomes in patients at high risk of being IVIG nonresponders (Kobayahi T, et al. Ped Infect Dis J 2009;28(6):498-502). Using a risk score to distinguish low (score <4) and high-risk patients (score >4), the investigators found that high risk patients had lower rates of treatment failures and CAA at 1 month if they received steroids. Future prospective studies will need to confirm the role of such risk stratification in the decision to start steroids for our patients with Kawasaki disease.
Chronic Fatigue Syndrome and a Potential Viral Cause

A potential retroviral link to chronic fatigue syndrome, known as CFS, a debilitating disease that affects millions of people in the United States has been recently found.  Researchers from the Whittemore Peterson Institute (WPI), located at the University of Nevada, Reno, the National Cancer Institute (NCI), part of the National Institutes of Health, and the Cleveland Clinic, report this finding online Oct. 8, 2009, issue of Science. 

Researchers have found evidence that a retrovirus named XMRV may be associated with Chronic Fatigue syndrome. While causality is yet to be proven, scientists identified XMRV DNA in the blood of 68 of 101 (67 percent) CFS patients in contrast to eight of 218 healthy people (3.7 percent). The virus, XMRV, was first identified in men who had a specific immune system defect that reduced their ability to fight viral infections and has also been found in patients with prostate cancer.   

The research team not only found that blood cells contained XMRV but also expressed XMRV proteins at high levels, produced infectious viral particles and retrovirus particles were seen by using transmission electron microscopy. A clinically validated test to detect XMRV antibodies in patients' plasma is currently under development.

Retroviruses like XMRV have also been shown to activate a number of other latent viruses. This could explain why so many different viruses, such as Epstein-Barr virus, which was causally linked to Burkitt's and other lymphomas in the 1970s, have been associated with CFS. This opens an exciting area for research and a potential way for specific therapy for this disease.
 
Lombardi VC, Ruscetti FW, Gupta JD, Pfost MA, Hagen KS, Peterson DL,  Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, and Mikovits JA. Detection of Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome. Online October 8, 2009. Science.

Bacterial Coinfections in Lung Tissue Specimens from Fatal Cases of 2009 Pandemic Influenza A (H1N1) --- United States, May--August 2009
During previous influenza pandemics, bacterial coinfections caused by S. pneumoniae, H. influenzae, S. aureus, and group A Streptococcus have been important contributors to morbidity and mortality. To help determine the role of bacterial coinfection in the current influenza pandemic, CDC examined postmortem lung specimens from patients with fatal cases of 2009 pandemic influenza A (H1N1) for bacterial causes of pneumonia. During May 1-August 20, 2009, medical examiners and local and state health departments submitted specimens to CDC from 77 U.S. patients with fatal cases of confirmed 2009 pandemic influenza A (H1N1).

Evidence of concurrent bacterial infection was found in specimens from 22 (29%) of the 77 patients. Ten cases with S. pneumoniae, six with S. pyogenes, seven with S. aureus, two with Streptococcus mitis, and one with H. influenzae; four of these 10 cases involved multiple pathogens. The median age of the 22 patients was 31 years (range: 2 months--56 years); 11 (50%) were male.

Seven of the 22 deaths (31.8%) were in children from ages 2 months to 15 years with a median age of 11 years. Only 2 of 7 children had underlying medical conditions reported, Down's syndrome and obesity. Five children were infected with a single bacterial pathogen. These bacterial pathogens were S. aureus in 3 children, S. pneumonia in one child, and Group A streptococcus in one child.  Two children were infected with two different bacterial pathogens: S. aureus and H. influenzae in one and Group A Streptococcus and S. pneumoniae in the second child.  For the 4 children with S. aureus, 2 isolates were identified as MRSA. The susceptibilities of the other 2 isolates were not available.  Two children had infection with 2 different bacteria, one with Group A Streptococcus and S. pneumoniae, and one with S. aureus (MRSA) and Haemophilus influenzae.

These data show that bacterial co-infections occurred in one-third of the children who were infected with the 2009 pandemic influenza A (H1N1) and who died from the disease.  MRSA was the most common bacterial pathogen.  Early recognition and treatment of bacterial coinfection in children with influenza-like illness may help decrease the mortality in 2009 pandemic influenza A (H1N1)-infected children.

MMWR Weekly Volume 58, No. 38 October 2, 2009.
Influenza-Associated Pediatric Mortality and Hospitalizations
Pediatric deaths

Since September 28, 2008, 147 reports of influenza-associated pediatric deaths were reported.  There were 28 deaths in children less than 2 years, 15 deaths in children 2-4 years, 45 deaths in children 5-11 years, and 59 deaths in individuals 12-17 years. Seventy-six of the 147 deaths were due to 2009 influenza A (H1N1) virus infections. The excess rates of death for 2008-2009 season as compared to the 2006-7 and 2007-8 influenza seasons are due to infection with the 2009 influenza A (H1N1) virus.

Of the 66 children who had specimens collected for bacterial culture from normally sterile sites, 23 (34.8%) were positive; Staphylococcus aureus was identified in 16 (69.6%) of the 23 children. Six of the S. aureus isolates were sensitive to methicillin, nine were methicillin resistant, and one did not have sensitivity testing performed. Twenty-one (91.3%) of the 23 children with bacterial coinfections were five years of age or older and 15 (65.2%) of the 23 children were 12 years of age or older.

Thirty-two (42.1%) of the 76 children with confirmed 2009 influenza A (H1N1) infection had a specimen collected from a normally sterile site; nine (28.1%) of the 32 children had a positive bacterial culture; seven of which were positive for S. aureus. Two of the S. aureus isolates were sensitive to methicillin, four were methicillin resistant, and one did not have sensitivity testing performed. Other bacteria identified include Streptococcus constellatus, Pseudomonas aeruginosa, Streptococcus, and Enterococcus.
 
Pediatric hospitalizations

The CDC also monitors influenza related hospitalizations due to influenza A, influenza B, and 2009 influenza A (H1N1).  During April 15, 2009 - October 3, 2009, preliminary laboratory-confirmed overall influenza associated hospitalization rates are as follows: 1) rates for children aged 0-23 months is 3.6, 1.6, and 1.3 per 10,000 2-4 years is 1.6 per 10,000, and 5-17 years is 1.3 per 10,000.  Rates for adults aged 18-49 years, 50-64 years, and ≥ 65 years, the overall flu rates were 0.8, 0.9, and 0.7 per 10,000, respectively.  One can see that all the rates for all children stratified by age group are higher than that of adults, with the highest rate in children 0-23 months old.

These data shows the importance on protecting children 6 months of age or greater with influenza vaccination.  For children less than 6 months of age who cannot be vaccinated, protection can be effected be ensuring that household members received influenza vaccine.
 
The CDC website published weekly updates on pediatric deaths and hospitalizations associated with influenza.
 
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In This Issue
Update on Influenza A (H1N1) 2009 Monovalent Vaccines
Novel H1N1 2009 Influenca Question
Florida Flu Hotline
2009 H1N1 Flu Situation Update
Nothing to Fear by the Flu Itself
Human Parechovirus
Kawasaki Disease: Clinical Pearls
Are Steroids Safe for Kawasaki Disease
Chronic Fatigue Syndrome and a Potential Viral Cause
Bacterial Coinfections in Lung Tissue Specimens from Fetal Cases of 2009 Pandemic Influenza A (H1N1)
Influenza-Associated Pediatric Mortality and Hospitalizations
Infectious Disease Newsletter Feedback
Fluconazole Dosing in Young Infants
Ontario's Experience with Universal Influenza Vaccines
Cat-Scratch Disease Update
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.

Inpatient Consultation:
All Children's Hospital
Tampa General Hospital
Bayfront Medical Center Nursery

Outpatient Clinics:
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Phone: 727-767-4160
Fax: 727-767-8270
Email: pidhl@allkids.org
Infectious Disease Newsletter Feedback
Please email your comments and suggestions so we may continue to improve our newsletter! 
Fluconazole Dosing in Young Infants
A recent pharmacokinetic study of fluconazole in young infants (</= 90 days) reveals that doses higher than commonly quoted in reference texts were needed to achieve adequate plasma concentrations of 2-4x's MIC's. According to Wade, KC, et al., their data suggests a treatment dose of fluconazole should be 12mg/kg/day in order to achieve therapeutic levels. Additionally, this study suggests that for early neonatal prevention of candidiasis fluconazole dosing at 3-6mg/kg twice weekly was safe and efficacious. For the late prevention of candidiasis, doses of 6mg/kg every 48 to 72 hrs (depending on gestational age and postnatal age) are reasonable.
Wade, KC et al. PIDJ. Vol 28 (8). 717-723.
Ontario's Experience with Universal Influenza Vaccines 
In 2000, the Canadian province of Ontario began offering all its citizens >/= 6 months of age free influenza vaccine. As a result, Ontario was able to increase the overall influenza vaccine rate in that province from 18% to 38% in a period of 4 years. For those aged >/= 65 years, vaccination rates increased from 60% to 75%. A 2009 study chose to look at the effect this change had on antibiotic prescription rates. The study found an overall decrease in influenza-associated antibiotic prescriptions of 64% (from 17.9 to 6.4 per 1000 people) in this time. Just another reason why getting your flu vaccine is a good idea.
Kwong, JC et al. CID 2009: 49 (1 September) 750-756.
Cat-Scratch Disease Update
Dr. Berman recently gave an excellent grand rounds lecture on cat-scratch disease, which you can view and receive free CME credit.

Some of the following pearls were extracted from his presentation:
  1. Most common in the southeastern U.S.
  2. Potential reservoirs include cats, dogs, ruminants & rodents.
  3. Cat fleas and ticks may be transmission vectors.
  4. Clinical presentations may include lymphadenopathy, FUO, hepatosplenic disease, Parinaud oculoglandular syndrome, encephalopathy, or osteomyelitis.
  5. Negative antibody assays or PCR (polymerase chain reaction) for Bartonella do not rule out infection, especially early in the clinical course.
  6. Antibiotic therapy is indicated for all immunocompromised patients, but efficacy varies for immunocompetent patients.  Outpatient antibiotic options may include azithromycin, rifampin, ciprofloxacin or trimethoprim/sulfamethoxazole.