Pediatric Infectious Disease Newsletter
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March 2010  

Malaria Acquired in Haiti - 2010
In 2008, a total of 1,298 cases of malaria in the United States were reported provisionally to CDC, and 527 (40.6%) were caused by P. falciparum; all but two of the malaria cases were imported.  Most imported cases are in travelers returning to the United States from areas in Africa, Asia, and the Americas where malaria transmission is known to occur.  Of the four Plasmodium species that routinely infect humans (P. falciparum, P. vivax, P. malariae, and P. ovale), P. falciparum causes the most severe disease and highest mortality.

Malaria caused by Plasmodium falciparum infection is endemic in Haiti, and the principal mosquito vector is Anopheles albimanus, which frequently bites outdoors. Although each year Haiti reports approximately 30,000 confirmed cases of malaria to the Pan American Health Organization, as many as 200,000 cases might occur annually.

On January 12, 2010, a 7.0 magnitude earthquake struck Haiti.  According to the Haitian government, approximately 200,000 persons were killed, and 500,000 were left homeless.  These displaced persons who are living outdoors or in temporary shelters as well as thousands of emergency responders in Haiti are at substantial risk for malaria.

During January 12 - February 25, 2010, CDC received reports of 11 laboratory-confirmed cases of P. falciparum malaria in 11 persons returning from Haiti. Patients included seven emergency responders (six U.S. military personnel, one nonmilitary emergency responder), one U.S. traveler and 3 Haitian citizens who traveled to the US, including one adoptee.  Two of the military personnel required intensive care.

Chemoprophylaxis was indicated for the seven emergency responders and the lone U.S. traveler. Six of these eight patients (including the two hospitalized military personnel) reported nonadherence to the recommended malaria medication regimen. Adherence status was unknown for the remaining two patients.

Prophylaxis:

Persons traveling to Haiti should receive chemoprophylaxis.  Chemoprophylaxis, although highly effective in preventing malaria, is not 100% effective.  Therefore, if fever develops in persons taking chloroquine or other antimalarials for chemoprophylaxis, they still should be evaluated for malaria infection with a diagnostic test.
  1. If preventive medications are started <1 week before departure, or while already in Haiti, either atovaquone-proguanil or doxycycline are recommended.
  2. Use of weekly chloroquine requires receiving the initial dose 1 week before departure.
  3. Use of weekly mefloquine requires receiving the initial dose 2 weeks before departure. 
  4. Mosquito avoidance measures should be taken, such as using mosquito repellent, wearing protective clothing, and sleeping under an insecticide-treated mosquito net.
Diagnosis:

CDC currently recommends microscopic examination of blood smears for malaria diagnosis. Three negative malaria smears spaced 12--24 hours apart are needed to rule out malaria. Rapid diagnostic tests for malaria can remain positive up to 3 weeks after treatment and should not be used to assess treatment failure in a patient with malaria.

Treatment:

Persons with laboratory-confirmed P. falciparum malaria acquired in Haiti should receive treatment according to CDC guidelines.
  1. Uncomplicated malaria can be treated with one of the following regimens: chloroquine, artemether-lumefantrine, atovaquone-proguanil, or the combination of quinine and doxycycline, tetracycline, or clindamycin.
  2. In patients with confirmed malaria who report adherence to chemoprophylaxis in Haiti, a change to a different drug than that taken for chemoprophylaxis is recommended for treatment. 
  3. Consider switching patients with uncomplicated, laboratory-confirmed malaria from chloroquine treatment to other recommended drugs after any indication of poor response to chloroquine such as increasing parasite density 24 hours after starting treatment, persistent parasitemia 48 hours after starting treatment, or clinical deterioration. 
  4. Severe malaria requires treatment with intravenous quinidine and one of the following: doxycycline, tetracycline, or clindamycin. Intravenous artesunate also is available from CDC for use in the United States as part of an investigational drug protocol.
 
MMWR 2010;59(08):217-219
 
Other references:

http://www.cdc.gov/malaria
 
CDC. Health information for travelers to Haiti. Atlanta, GA: US Department of Health and Human Services, CDC; 2010. http://wwwnc.cdc.gov/travel/destinations/haiti.aspx
Accessed March 2, 2010.
Do Parents Remain Concerned about Vaccine Safety?
In the March 2010 issue of Pediatrics, Freed et al, conducted an Internet survey in 2009 assessing parental vaccine safety concerns.  Parents were enrolled if they had children living in the household <= 17 years of age. Outcome measures included opinions on vaccine safety and whether or not a vaccine that a physician recommended was refused.
 
Ninety percent of the 1552 parents that responded to the survey agreed that vaccines are a good way to protect their child from disease.  Eighty-eight percent follow their physician's recommendations regarding vaccines.  However, 11.5% had refused at least one vaccine that their physician recommended.  Fifty-four percent of those surveyed were concerned about adverse events. Newer vaccines appeared to be more of a concern to parents (HPV and the conjugated meningococcal vaccine). Other specific vaccine refusals were MMR and varicella.   Thirty-one percent of the parents felt they should have the right to refuse vaccines for school entry. Eleven percent believed children did not need to be vaccinated for diseases that are no longer common and >1 in 5 believe that some vaccines cause autism in healthy children.
 
The bottom line is that we still need to continue to educate families about vaccine preventable diseases vaccines as well as the safety record of vaccines.  Physicians remain a trusted source of information for families.
 
Pediatrics 2010;125:654-659
Dealing with Parental Refusal to Vaccinate
This AAP webpage offers useful guidance and downloadable documents, including a parental Refusal to Vaccinate Form.
 
http://www.aap.org/immunization/pediatricians/refusaltovaccinate.html
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.

Thank you for your participation.
 
www.allkids.org/vaccinesurvey
Vaccine and Influenza Resource Links
Vaccine information from the Centers for Disease Control and Prevention
www.cdc.gov/vaccines/pubs/vis/default.htm
 
Influenza H1N1 Resources for Pediatricians
For guidance documents:
www.cdc.gov/h1n1flu/guidance/
Information for Healthcare Professionals:
www.cdc.gov/h1n1flu/clinicians

Oseltamivir Safety in Children < 12 Months of Age for Treatment of Influenza
Oseltamivir has been reported to cause CNS toxicity in 7-day-old rats with a single super dose of 1000 mg/kg dose. However, this is not seen in adult animals. This adverse outcome may be secondary to the immature blood-brain barrier in juvenile rats.
 
A retrospective study was done to compare neurologic adverse events that occurred with oseltavmivir compared to the adamantanes (amantadine and rimantadine) in children <12 months of age.
 
Fifteen academic centers participated between 2000-2006.  Data was collected for adverse events occurring within 30 days of oseltamivir. There were a total of 180 patients included in the study.
 
There was not a statistical difference between oseltamivir and the adamantanes regarding abnormal neurologic events. Two patients had a seizure and one patient had seizure-like activity.  Investigators deemed these events unrelated to the antiviral medication. Of the 3 patients, one had pertussis and influenza co-infection and had seizure-like movements on day 2 of amantadine. The second patient had respiratory failure and the first seizure occurred prior to oseltamivir.  The last patient had a seizure during amantadine treatment but had an underlying history of seizures.  One death occurred within 30 days in a patient that received oseltamivir. This patient had life-support withdrawn by the family due to the history of pre-existing interstitial lung disease and failure to thrive.
 
This is the largest report of oseltamivir use in children <12 months of age. There is a prior publication from Japan of 103 children treated with oseltamivir. In these children there was no mortality or encephalopathy.
 
In the current study, there was a broad dosing range among oseltamivir-treated patients (1-7mg/kg/dose). This emphasizes the importance of additional pharmacokinetic data to determine the most appropriate dose. Currently, the Collaborative Antiviral Study Group is conducting a prospective pharmacokinetic and safety study among the pediatric population < 2 years of age.
 
Pediatric Infectious Disease Journal 2010; 29:195-198
Risk Factors for the Development of Herpes Zoster Following Varicella Vaccine
This study was aimed to investigate effects of chronic medical conditions, race, and recent vaccination on the risk of developing herpes zoster (HZ) in children that had received one prior dose of varicella vaccine. A prior publication in 1998 in adults suggested the risk of HZ in African-American adults was 1/3 that of Caucasians.
 
In this current study, cases were identified from a cohort of members of the Southern California Kaiser Permanente (SCKP) Health Plan.  With this health system, there is an opportunity to evaluate outcomes in patients of all races since there is equal access for all that participate in SCKP. 
 
During the years 2002-2008, 122 children were diagnosed with HZ that were <12 years of age. Control subjects without HZ during the same time period were matched 5:1 ratio to each case.  The investigators found the risk of HZ among African-American children was 40% of that among Caucasian children and 30% of that among Asian children.  These results may support a hypothesis of genetic differences in immunity to varicella.
 
Pediatric Infectious Disease Journal 2010;29:205-208
Are We Following Recommendations for Newborns Exposed to HbsAg-Positive Mothers?
As we all know, the risk for developing chronic hepatitis B infection in infants is very high (about 90%) following maternal-infant transmission.  A study was conducted in Switzerland to evaluate the compliance with recommended procedures of exposed infants.
 
Records were reviewed to determine hepatitis B testing from four sites over a two-year period (2005 and 2006). 26,750 (98.6%) women were tested for hepatitis B. 194 women were HBsAg positive (0.73%).  53 were excluded from the study. Of the remaining 141 women, 84% were foreign born.  If the infant was Swiss born, then they were more likely to complete timely immunization than if they were foreign born. 98.6% of newborns received active and passive anti-HBV immunization within 24 hours of birth. Of the HBsAg-exposed infants, 83% completed vaccine with 2 further doses but this was not done in a timely fashion. Delay of the 2nd dose was observed most often.
 
Breakdown from the 4 sites:
 
17% did not complete the hepatitis B vaccine series
35% completed the series but not in a timely fashion
48% completed the series as recommended
 
As far as following recommendations for serologic follow-up, only 38% were tested at all and 22% were tested in a timely fashion.
 
The good news: no chronically infected child was identified. However, this study further reinforces the importance of long-term follow-up in infants born to mothers infected with hepatitis B.
 
Reminders need to be sent to physicians for recommended procedures in managing infants born to hepatitis B-infected mothers.  The other important point in this study from the four Swiss hospitals was that 0.73% of the mothers were HBsAg positive.
 
Pediatric Infectious Disease Journal 2010;29:248-250
Hyperbaric Oxygen Therapy (HBOT) in Pediatric Infectious Disease Practice
Some pediatric patients with chronic decubitus ulcers and/or refractory osteomyelitis may benefit from HBOT. One role of HBOT in the healing process is to create a high oxygen gradient from the periwound area to the hypoxic wound center to stimulate neoangiogenesis and promote wound healing.  We have patients that have benefited from HBOT in combination with surgical debridement and antibiotics.  Benefits of HBOT also include enhancement of oxidative killing of bacteria, enhanced collagen production and deposition, and potentiation of antibiotics. 
 
The Cochrane Collaboration found 26 studies examining HBOT role in management of chronic wound healing. Only 5 studies were considered rigorous to be considered for full review.  The Undersea and Hyperbaric Medical Society (UHMS) has approved specific indications for HBOT. These include air or gas embolism, decompression sickness, gas gangrene, crush injuries, intracranial abscess, necrotizing soft tissue infections, radiation necrosis, compromised skin grafts and refractory osteomyelitis.
 
HBOT is not without risk. Adverse events are rare but have been reported. They include barotrauma to sinuses (<2%), ears (2-4%), and lungs (pneumothorax <1 in 1 million). Patients with myopia may have a temporary exacerbation and generalized seizures may occur in 0.03% of patients.  Therefore, it is very important to only consider HBOT for the approved indications.  Children treated with HBOT may only be cared for by a certified and experienced physician in HBOT and wound management. It is the combination of interventions (HBOT, wound debridement, and antibiotics) that allow for healing to occur. Chronic fatigue, lyme disease, fibromyalgia, and autism are not approved for HBOT.
 
Wounds 2010;22(1):1-11
Domestic Medical Screening for Haitian Orphan Parolees
The Department of Health and Human Services has made recommendations for medical screening for orphaned children from Haiti entering the United States under humanitarian parole status.
 
The initial medical screening should include:
 
Assessing for symptoms of communicable disease and trauma
Past medical history of tuberculosis and HIV should be solicited if possible medication and immunization history if available.
 
If the child has fever, the physician should have high clinical suspicion for malaria, dengue, and S. typhi infection (Typhoid fever).
 
Lab screening should include:
 
  • CBC, HIV testing, malaria smear (if symptomatic), leptospirosis serology (if symptomatic), dengue serology (if symptomatic), stool (ova and parasite on three consecutive mornings regardless of symptoms)
  • If GI symptoms are present, send for stool culture, Giardia, Cryptosporidium, rotavirus, and strongyloides (if eosinophilia is present)
  • RPR (if positive, then FTA-ABS or MHA-TP)
  • Hepatitis B surface antigen
  • Tuberculin skin testing (TST) or interferon-gamma release assay (2-14 years of age)-some experts prefer TST in children < 5years of age.

Vaccination recommendations:
 
There are low vaccine coverage rates in Haitian orphans. It may be preferred to reimmunize children presumptively. It is acceptable to perform serologic evaluation of concentrations of antibodies to vaccines (examples: measles, mumps, rubella, polio, hepatitis A, tetanus and diphtheria).
 
Mental Health Recommendations
 
Consider potential mental health and developmental issues in all Haitian orphans.
 
For further recommendations see the detailed document:
www.cdc.gov/immigrantrefugeehealth/exams/recommendations-domestic-medical-screening-haitian-orphan.html
 
Department of Health and Human Services February 2010
Perinatal HIV-1 Infected Children Born to Low Risk Mothers Who Tested Antibody Negative During Pregnancy
This article reviews 3 cases of HIV-1 infected infants born to low risk mothers who tested HIV-1 antibody negative during the 1st trimester of pregnancy. We have had the same experience in our infectious disease group.  Although the rate of perinatal HIV infection has dropped dramatically in the United States, there still remain children born with perinatal infection. The current guidelines recommend HIV-1 testing of all pregnant women during the first trimester. Recommended repeat testing should be carried out during the 3rd trimester for a subset of pregnant women (however, there is a statement that testing may be considered for all pregnant women).
 
The subset of women included for third trimester testing:
 
IV drug users and partners
Prostitution
Multiple sexual partners
Women that receive care in jurisdictions with higher incidence HIV/AIDS
 
The three case presentations in this report (all low risk mothers testing HIV negative in 1st trimester):
  1. 5-month-old infant presents with FTT, adenopathy, thrombocytopenia, and anemia. The mother acquired infection from the patient's father who was HIV positive but did not disclose to the mother.
  2. 5-month-old infant presents with Pneumocystis jiroveci pneumonia (PCP).  The mother acquired the disease from the patient's father who was involved in a bisexual relationship.
  3. 3-month-old infant presents with Pneumocystis jiroveci pneumonia (PCP).  The father was subsequently diagnosed with AIDS.
These 3 cases occurred in Ohio, a state that does not have an elevated incidence of HIV or AIDS as per 2006 CDC report.  These cases demonstrate that infection may occur later in pregnancy and go undetected.  Repeat testing during the 3rd trimester may potentially prevent 46 infant infections annually.  The pediatrician should continue to remain vigilant regarding HIV testing in any infant suspected to have HIV infection despite negative maternal testing.
 
Pediatric Infectious Disease Journal 2010;29:274-275
Severe Isoniazid-Associated Liver Injuries Among Persons Being Treated for Latent Tuberculosis Infection-United States 2004-2008
Approximately 4% of the U.S. population has latent tuberculosis infection (LTBI). Because LTBI can progress to active disease, CDC recommends testing and treatment of LTBI for persons in certain groups. Since the 1960s, 6 to 9 months of isoniazid (INH) has been the mainstay of treatment for latent tuberculosis infection (LTBI), but its application has been limited by concerns about the toxicity of INH and the long duration of treatment.  To quantify the frequency of severe adverse events (SAEs) associated with LTBI treatment, the CDC began a national project to monitor SAEs associated with treatment for LTBI. 

From 2004--2008, 17 SAEs in persons who received INH therapy for LTBI and had experienced severe liver injury were reported to the CDC through the CDC's passive surveillance system. Two persons were children (11 and 14 years old), 5 persons were between 16 and 35 years and 10 persons were older than 35 years.  Five patients, including one child, underwent liver transplantation. Five adults died, including one liver transplant recipient.

Timing of SAEs:

Nine of the 17 SAEs occurred beyond the third month of therapy, indicating that INH-associated liver injury is possible anytime during the treatment course. This finding was in contrast to an earlier study that found 10 of 11 episodes of INH-induced hepatotoxicity occurred during the first 3 months of therapy.

The CDC obtained further information on 10 of the 15 cases with LTBI.  SAE symptoms began in the 10 patients 1 to 7 months after INH initiation.  All patients were monitored according to current guidelines (i.e., monthly clinical evaluation, including symptom screening and physical examination, and two patients were selected for additional laboratory monitoring.  SAE diagnosis was prompted by symptoms, not laboratory values. Additionally, three patients had no putative predictors of liver injury, indicating that careful monitoring is needed regardless of the patient's risk factor profile. 

Current recommended treatment for LTBI:

LTBI treatment remains a key component of the TB elimination strategy in the US. One study estimated that LTBI treatment prevented 4,000 - 11,000 TB cases in 2002 in the US, substantially reducing the burden of TB.

Until an equally effective, better-tolerated regimen is developed, 9 months of INH therapy remains the mainstay of LTBI treatment.  Efficacy and safety have not been established for other treatment regimens, such as 4 or 6 months of rifampin, 3 months of INH and rifampin (the preferred regimen in the United Kingdom, or 3 months of once-weekly INH and rifapentine, a regimen currently under investigation.

Advice for medical providers:
  1. Patients receiving INH for LTBI therapy should be monitored according to American Thoracic Society (ATS)/CDC recommendations because of the risk for drug-induced hepatoxicity.
    1. Existing recommendations emphasize the careful selection of candidates for LTBI testing and treatment based on risk for infection. Persons who are not at risk for TB infection should not undergo testing for LTBI. 
    2. Monthly clinical monitoring, including a brief physical examination, for the signs and symptoms of LTBI treatment--associated adverse events is recommended for all patients. 
    3. Patients who have HIV infection, patients who have chronic liver disease, pregnant women, women in the immediate postpartum period (≤3 months after delivery), and patients who use alcohol regularly should be considered for baseline laboratory hepatic testing.
    4. Although baseline laboratory testing is not routinely indicated in older persons, it may be considered on an individual basis, especially for patients who are taking medications for chronic medical conditions.
    5. Routine laboratory testing is indicated for patients whose baseline testing is abnormal and other persons at risk for hepatic disease.
    6. An evaluation including laboratory testing should be obtained upon the first sign or symptom of a possible adverse event. Providers should educate patients to discontinue treatment immediately, even before an evaluation is conducted.
    7. In the absence of symptoms, INH should be discontinued if aminotransferase values are five times the upper limit of normal. 
    8. In the presence of symptoms, INH should be discontinued if aminotransferase values are three times the upper limit of normal.
  2. No more than a 1-month supply of INH at a time should be prescribed, and treatment should be combined with careful clinical monitoring.
  3. INH-associated liver injury is an idiosyncratic drug-induced reaction in patients of any age treated with INH, including those with or without a putative predictor for INH-associated liver injury.
  4. INH-associated liver injury can occur even in the absence of symptoms.
  5. Patients receiving INH therapy for LTBI should be told categorically by medical providers to stop taking their medication immediately if they have symptoms such as nausea, vomiting, abdominal discomfort, or unexplained fatigue and to contact their providers for further evaluation.
  6. Report possible INH-associated SAEs to their respective health departments and to the Food and Drug Administration's MedWatch (https://www.accessdata.fda.gov/scripts/medwatch).
 
MMWR 2010;59(08):224-229
 
Additional references:
 
American Thoracic Society. An official ATS statement: Hepatotoxicity of Antituberculosis Therapy. Am J Respir Crit Care Med 2006;174:935--52.
 
Pediatrics Tuberculosis Collaborative Group. Targeted tuberculin skin testing and treatment of latent tuberculosis infection in children and adolescents. Pediatrics 2004;114:1175--201.
 
CDC. Targeted tuberculin skin testing and treatment of latent tuberculosis infection. MMWR 2000;49(No. RR-06).
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In This Issue
Malaria Acquired in Haiti - 2010
Do Parents Remain Concerned about Vaccine Safety?
Dealing with Parental Refusal to Vaccinate
Take Part in Our Vaccine Survey
Vaccine and Influenza Resource Links
Oseltamivir Safety in Children < 12 Months of Age for Treatment of Influenza
Risk Factors for the Development of Herpes Zoster Following Varicella Vaccine
Are We Following Recommendations for Newborns Exposed to HbsAg-Positive Mothers?
Hyperbaric Oxygen Therapy (HBOT) in Pediatric Infectious Disease Practice
Domestic Medical Screening for Haitian Orphan Parolees
Perinatal HIV-1 Infected Children Born to Low Risk Mothers Who Tested Antibody Negative During Pregnancy
Infectious Disease Newsletter Feedback
What is the Value of Commercial Influenza Assays for Detecting Pandemic Influenza A (H1N1) in Pediatrics?
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:
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Phone: 727-767-4160
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Email: pidhl@allkids.org
Infectious Disease Newsletter Feedback
Please email your comments and suggestions so we may continue to improve our newsletter! 
What is the Value of Commercial Influenza Assays for Detecting Pandemic Influenza A (H1N1) in Pediatrics?
Investigators from Children's Hospital of Boston collected nasopharyngeal specimens using two swabs from each patient in children up to 18 years of age. Two test kits were used. One kit was Binax NOW and the other Simulfluor Flu A/B, which is a direct fluorescent antibody.  Polymerase Chain Reaction (PCR) was used as the standard. 
 
Even though the specificity of each test was >99%, both tests had poor sensitivity for the Pandemic H1N1 (BinaxNOW 59.6% and DFA 57.3%).  Therefore, it is important to remember that your rapid testing may not rule out infection with Pandemic H1N1. PCR is much more sensitive.
 
Pediatric Infectious Disease Journal 2010;29:261-262