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Pediatric Infectious Disease Issues: Smallpox, Combination Vaccines and Methicillin-resistant Staphylococcus aureus

Authors: Jorge M. Quinonez, MDFaculty and Disclosures


Smallpox: Back to the Future

Smallpox is a highly communicable disease caused by variola, a DNA virus member of the Orthopoxvirus genus.[1,2] As recently as the late 1960s, millions of smallpox cases per year were still reported in Asia and Africa. During the following decade, worldwide immunization efforts were successful in eradicating the disease. The last known wild case of smallpox in the world occurred in Somalia in 1977, and the last wild case in the United States occurred in 1949.[1] In 1971, it was deemed that the risk of serious side effects from the vaccine was higher than the risk of exposure to smallpox, and routine vaccination was discontinued in the United States. Routine vaccination of healthcare workers was subsequently discontinued in 1976. In 1990, smallpox vaccination of US military personnel also ended.[1-3]

Smallpox is mainly transmitted from aerosol droplets of infected individuals. It can also be transmitted by direct contact with infected lesions or through fomites contaminated with the virus (clothing or bed linens). The incubation period is 7-17 days, with a mean of 12 days. The contagious state in the patient begins with the appearance of an enanthem and a characteristic exanthem. This exanthem is characterized by macules progressing to papules, vesicles, and pustules.[1,3] Most patients are ill enough during the prodromal period to seek medical attention and to be admitted to the hospital. For this reason, household contacts and healthcare professionals are likely to be secondary cases. Young children, pregnant women, and the elderly have the worst prognosis when confronted with the disease.[1]

Immunization Against Smallpox

Even though the disease was deemed eradicated, stocks of virus were retained in government-run laboratories in the United States and the former Soviet Union. The smallpox vaccine was recommended exclusively for those laboratory workers and research personnel likely to come into contact with the virus.[1,3] Individuals who were immunized prior to 1972 are likely not to be fully protected against the disease since the concentration of protective antibodies declines significantly after 5-10 years.[1]

The only vaccine currently available in the United States is a live-virus vaccine; it does not contain the variola virus, but rather a related virus, vaccinia. Inoculation with vaccinia virus stimulates an immune response that cross-reacts with variola and protects the recipient.[1,3] The 30-year-old Dryvax (Wyeth-Ayerst Laboratories) vaccinia vaccine can effectively be used in adults, but no pediatric clinical trials have been conducted.[4]


There is no known successful antiviral therapy for smallpox, although cidofovir may offer some help. Most of the treatment is limited to supportive measures and preventing secondary bacterial infections.[1,2]

Smallpox: A Potential Biological Warfare Agent

The issue of smallpox was laid to rest for several years. Although no new wild cases have been reported, recent concern arises from reports that before the dissolution of the Soviet Union, smallpox was being developed as a weapon of biological warfare. In addition, there is fear that the virus and the expertise to propagate it may have fallen into terrorist hands.[1,2,5] These concerns, together with the recent terrorist attacks on US soil, have revived interest in the disease. The US government was forced to develop a plan of immunization as a result of the potential threat of smallpox being introduced into the country by a bioterrorist attack.[6]

The US Federal Immunization Plan

Raymond Strikas, MD,[7] Director of Smallpox Preparedness and Response Program, of the Centers for Disease Control and Prevention, Atlanta, Georgia, described and discussed the federal plan for immunization against smallpox. This plan is for the immunization of the civilian response healthcare teams, not the general public. This population was targeted because half of all new cases occur in healthcare facilities, he explained. By reducing the chances of transmission in those settings, the overall transmission of the disease is significantly diminished. The vaccine was to be administered to public health and hospital personnel identified by each individual State Health Department. It was also to be offered on a voluntary basis to hospital personnel.

Currently, 38,577 civilians have been vaccinated; 24,974 of those are state health employees and 11,661 are private health employees, and 2174 hospitals in the United States have at least 1 employee vaccinated against smallpox, which accounts for 44% of the total number vaccinated in the country. The federal government has spent approximately $2.5 billion for State preparedness.

Side Effects of Vaccine

Surprisingly, no reports of the most feared complications of the vaccine -- eczema vaccinatum, progressive vaccinia, and fetal vaccinia syndrome -- have been reported. However, 6 civilian and 56 military vaccinees reportedly developed myocarditis; it is likely that these are directly related to the vaccine. Thus, individuals receiving the vaccine should be closely monitored, and those with known cardiac problems should not receive the vaccine.

Vaccination of Children

Dr. Strikas emphasized that there are currently no recommendations for vaccination of children. In addition, no pediatric trials of vaccine safety are under way or planned. One of the biggest concerns about vaccinating children is the potential for serious side effects. Historically, children aged 1-4 years have had the highest incidence of complications among vaccinated individuals.[7]

The American Academy of Pediatrics issued a policy statement in October 2002 regarding smallpox vaccination, in which it recommended the ring immunization approach if an outbreak should occur.[1,2, 4] If smallpox were introduced by way of an act of terrorism, the infected index cases would be isolated. Their contacts and contacts of the latter would be identified and immunized by trained teams of healthcare professionals. This method is based on the fact that an immunization dose given within 3-4 days of disease exposure can prevent or ameliorate the disease. This plan would contain local outbreaks without submitting large numbers of the pediatric population to the complications of vaccine administration.[1]

One of the major concerns is that the majority of present-day clinicians have never actually seen a case of smallpox; therefore, it is imperative that pediatricians become aware of the signs and symptoms of smallpox as well as the potential side effects of the vaccine. This clinical acumen could have a major impact in the event of a true crisis.

New Combination Vaccines for Childhood Diseases

The current childhood immunization schedule in the United States requires 20 injections in the first 2 years of life. Pediatricians are at times faced with the dilemma of having to administer 5 injections in a single health visit.[8] The problem is likely to worsen with the potential near-future development of additional vaccines for use in infancy (eg, conjugated meningococcal and rotavirus vaccine). This situation has prompted the development of combination vaccines. Combination vaccines provide simplicity, convenience of administration, easier storage, decreased number of injections and office visits, increased compliance with immunization schedules, and easier record keeping.[9,10]

However, the combination of multiple vaccine antigens presents several challenges. It should be recommended that the components of the vaccine be administered at the same time. However, the reactogenicity and potential side effects of the combined antigens have not yet been determined. Since there is the potential for physical and chemical interaction among the vaccine components and the buffers and preservatives, the immunogenicity of each component needs to be addressed to determine whether these are similar to and as effective as the components given individually.[10]

DTaP3/IPV/Hepatitis B Virus (HBV)

Margaret B. Rennels, MD, FAAP,[11] Professor of Pediatrics, University of Maryland School of Medicine, Baltimore, discussed the newest combination vaccine approved by the US Food and Drug Administration (FDA): DTaP3/IPV/HBV vaccine (Pediarix, Glaxo SmithKline Biologicals). This vaccine may be used to complete the primary series; it is not to be used as a booster vaccine. Although DTaP3/IPV (inactivated poliovirus)/HBV is a new vaccine, it does not include any new antigens.

Dr. Rennels emphasized the need to continue the birth dose of hepatitis B vaccine for public health purposes, implying that a number of patients will receive 4 doses of HBV vaccine, which has been determined to be safe with regard to immunogenicity and adverse reactions.

Another vaccine, DTaP5/IPV/haemophilus type b (HBV) (Aventis Pasteur), is currently in development and pending FDA approval. In the largest US study of this vaccine, 400 infants received DTaP5/IPV/HBV concurrently with H influenzae type b (Hib) vaccine at 2, 4, and 6 months of age. Infants in the control groups received DTaP and HBV vaccine (alone or in combination), Hib, and either IPV or oral polio vaccine (OPV) at the same time intervals. Antibody levels were measured at 7 months of age, and although there were variations in the geometric mean antibody levels, no significant differences in seroprotection or vaccine response were noted.[8,12]

In an additional lot-consistency study conducted in the United States, infants received DTaP3/IPV/HBV concomitantly with Hib at 2, 4, and 6 months of age. At 7 months of age, 99% to 100% of the 363 infants had protective antibodies against diphtheria, tetanus, HBV, and Hib; 89.0% to 99.7% had a response to pertussis antigens.[8,13]

Dr. Rennels mentioned that the antibody response to hepatitis B surface antigen (HBSAg) has been noted to be lower in some DTaP3/IPV/hepatitis B-immunized patients compared with patients given the monovalent component of the vaccine at 0, 1, and 6 months of age.[11] Although this finding probably has no clinical or biological significance, she said that for this reason some experts prefer to stick with a monovalent vaccine for infants born to HBSAg-positive mothers.

Reactogenicity to the vaccine was evaluated in a multicenter study conducted in Germany in which 3029 infants received the DTaP3/IPV/HBV vaccine combined with Hib at 3, 4, and 5 months of age.[8,14] The patients were monitored for solicited local and general side effects for 4 days after each injection and for unsolicited side effects for 30 days. They were compared with patients who received administration of the vaccines individually. A greater number of patients who received the DTaP3/IPV/HBV vaccine reported low-grade fever than those who received individual vaccines, but other side effects, such as increased crying and irritability, were seen more frequently in patients who received the monovalent vaccine. Dr. Rennels concluded by adding that the DTaP3/IPV/HBV vaccine cost will be covered by the Vaccine for Children Program.

Methicillin-resistant Staphylococcus aureus (MRSA) Infection

The first case report of MRSA infection in the United States occurred in 1968.[15] The initial infections occurred exclusively in hospitals and mainly in critical care units, and traditionally they were thought to occur almost exclusively in the nosocomial setting.[15,16]

In 1980, the first community-acquired MRSA (CA-MRSA) infection was reported in the United States.[15,17] For the next 2 decades, cases of CA-MRSA were restricted to patients with specific risk factors: residence in a long-term care institution, intravenous drug abuse, and recent hospitalization or surgery were particularly susceptible.[15,16,18]

During the past few years, however, increasing accounts of colonization and infection with CA-MRSA in children and adults who lack predisposing risk factors have been noted across the country.[15,16,19] Although the clinical spectrum of the CA-MRSA infection is very similar to that of infection caused by the strains of the bacteria that are susceptible to methicillin, with predominance of skin and soft-tissue involvement, increasing numbers of invasive disease with CA-MRSA are being reported. These findings have prompted researchers and clinicians to think that in addition to antibiotic resistance, the organism may be particularly virulent.[15,19]

CA-MRSA on the Rise

Sheldon Kaplan, MD,[20] of the Department of Pediatrics, Baylor College of Medicine, Hosuton, Texas, provided insight into the recent and alarming increase in the rates of nosocomial and CA-MRSA infection. From 1989 to 2001, 50% of nosocomial S aureus infections in adults were due to MRSA strains. In 1995, the rate of S aureus infections that were due to MRSA strains in pediatric intensive care units throughout the United States was 10%; this rate jumped to 30% in 2001.[20]

Dr. Kaplan emphasized what a problem CA-MRSA has become, with most areas of the country reporting up to 45% of infections caused by community-acquired S aureus as methicillin-resistant. He noted that in the Houston area where he practices, up to 70% of S aureus infections in children in the community are due to CA-MRSA. Similar numbers are being reported from other areas of the world, mainly Latin America.

Treatment of CA-MRSA Infection

The CA-MRSA isolates have shown different antibiotic susceptibility patterns compared with MRSA strains isolated from hospitals. The former have tended to be susceptible to different, unrelated antibiotics such as clindamycin, gentamicin, and trimethoprim-sulfamethoxazole, while the latter typically show resistance to these antibiotics.[19,21,22] The majority of reports of CA-MRSA infection from different regions of the United States report uniform sensitivity to clindamycin; however, recent information from some areas in the country report clindamycin resistance in more than 25% of their CA-MRSA isolates.[19,23]

The emergence of CA-MRSA has dramatically modified the initial choice of antibiotic coverage when significant infection by these organisms is suspected. The beta-lactam antibiotics that traditionally have been used for these types of infections are generally ineffective in treating MRSA strains.[15] In those regions where CA-MRSA strains are frequently found, oral clindamycin has been recommended as first-choice empiric therapy in patients with skin and soft-tissue infection who are not critically ill. An alternative approach in well-appearing children is to obtain a culture and use a beta-lactam antibiotic initially and change to oral clindamycin if no clinical improvement is achieved or if dictated by the antibiotic susceptibility of the isolated strain. For children who are critically ill, initial empiric therapy should be provided with intravenous clindamycin or vancomycin, likely combined with a third-generation cephalosporin to broaden the coverage to other organisms.[15,16,19]

Physicians should be well aware of the susceptibility patterns of the strains circulating in their communities. There is great concern about CA-MRSA infection because of its increased virulence; death or other serious sequelae can occur if the appropriate antibiotic therapy is not promptly instituted. In areas where clindamycin resistance by CA-MRSA isolates approaches 10% to 15%, only vancomycin should be used for severe infections suspected to be due to this organism. Linezolid, a new oxazolidone antibiotic, may offer an alternative for patients who do not tolerate vancomycin.[19]


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