diff --git "a/notes/Ghai-Essential-Pediatrics_6.txt" "b/notes/Ghai-Essential-Pediatrics_6.txt" new file mode 100644--- /dev/null +++ "b/notes/Ghai-Essential-Pediatrics_6.txt" @@ -0,0 +1,2141 @@ +current data on immunogenicity and safety is insufficient to recommend its use. +An oral vaccine has been developed that contains live attenuated bacteria of the Ty21a strain of S. typhi. A genetically stable mutation makes it unikely for the bacteria to revert to a virulent form. The vaccine is available as an enteric capsule containing 2-6 million live lyophilized bacteria that induce intestinal mucosal immunity. Primary immunization, consisting of 3 doses given on alternate days on an empty stomach, has an efficacy of 50-60% within 7 days of completion of the schedule. Since the bacteria are inactivated by gastric acidity, capsules must be swallowed intact. Hence, the vaccine is unsuitable for children younger than 6 yr. Antibiotics should not be given between 3 days before to 7 days after the vaccine administration to avoid interference with vaccine 'take'. The vaccine is contra­ indicated in children with significant immunodeficiency. Mild adverse effects include abdominal discomfort and fever. Vaccination has to be repeated every 3 yr. The vaccine is not available in India. + +Hepatitis A Vaccine +Infection with hepatitis A virus is endemic in India and is usually benign in children below 5 yr of age, with the majority (50-85%) presenting with minor manifestations like any viral illness. Disease severity, complications and mortality are higher in those with underlying chronic liver disease, adolescents and adults. +The available vaccine contains formalin inactivated viruses grown on human diploid cell lines. Each pediatric dose of the vaccine has an antigen content of 720 ELISA units and aluminium hydroxide as an adjuvant. The vaccine has protective efficacy of 95-100%. Since maternal antibody may interfere with immune response to the vaccine, the vaccine is avoided in infancy (Box 9.10). A combined vaccine containing hepatitis A and B vaccines may be used in a three dose schedule. +The hepatitis A vaccine is not recommended for universal immunization since the diseases prevented is usually benign and of less public health relevance. However, with improvement in hygiene, the infection is increasingly acquired at later age and may be symptomatic, sometimes with fulminant hepatic failure. Hence, IAP receommeds its administration to all children. The vaccine should + + +Box 9.10: Hepatitis A vaccine +Dose, route 0.5 ml, intramuscular Site Deltoid +Schedule +National Program Not included +IAP 2012 Two doses beyond 1 yr of age, given 6 +mo apart +Catch up Complete two dose series with interval +of �6 mo; if �10-yr-old, screen for HAV antibody first, administer vaccine only if +seronegative; use adult vaccine (1440 +units) if �13-yr-old +Adverse reactions Local pain; nausea, anorexia, malaise Contraindication Anaphylaxis after previous dose +Storage 2-8°C; protect from light; use within 30 +min of reconstitution + + +particularly be considered in children with chronic liver disease who are seronegative for HA virus, children attending creches and day care facilities, travelers to endemic areas and in adolescents who are known to be seronegative for HA virus. The vaccine is effective if administered to rnunized household contacts of patients symptomatic with HA V within the last 10 days. +A live attenuated vaccine has become available in India. Two doses of 1 ml each are administered subcutaneously with an interval of 6 months between the doses. + +Rotavlrus Vaccine +Rotavirus is a major cause of diarrhea related morbidity and mortality in children worldwide. Of the 7 known serogroups (A-G), group A rotaviruses cause most human disease. Epidemiologic studies indicate that rotavirus is responsible for 6-45% of diarrheal illnesses requiring hospital admission in Indian children. Rotavirus infections usually affect young infants, and natural infections do not protect against re-infection or severe disease. The first licensed rotavirus vaccine (Rotashield), a live oral tetra­ valent vaccine, was withdrawn soon after its introduction in 1998 due to occurrence of vaccine associated intus­ susception. Two live oral vaccines, namely Rotarix and RotaTeq, are currently marketed worldwide. +Rotarix is a monovalent (RVl) live attenuated vaccine containing the human rotavirus GIP (8) strain attenuated by culture in Vero cells. Each dose has at least 106 median cell culture infective dose (CCID50), and is given in orally in a 2 dose schedule (Box 9.11). RotaTeq is a pentavalent (RVS) vaccine consisting of strains reassorted between the bovine and human WC3 rotaviruses containing specific VP7, VP4 and/ or G6 proteins, and attenuated by culture in Vero cells. Each dose of the vaccine contains a minimum titre of 2-2.8 x 106 infectious units per reassortant and not greater than 116 x 106 infectious units per aggregate dose, suspended in a solution of buffer and stabilizer. Itis administered orally in a three dose schedule at 2, 4 and 6 months. +Immunization and Immunodeficiency + + + +Box 9.11: Rotavirus vaccine +Dose, route RVl: 1 ml (lyophilized) or 1.5 ml (liquid); RVS: 2 ml (liquid); oral +Schedule +National Program Not included +IAP 2012 RVl: 2 doses; RVS: 3 doses; at6-14weeks c.4weeks apart; maximum age <15 weeks for the first dose and <8 mo for the final dose; do not begin schedule at ?.15 weeks +Adverse reactions Intussusception (rare) +Contraindication Past history of intussusception; severe immunodeficiency +Precaution Postpone vaccination during ongoing diarrhea or moderate illness +Storage 2-8°C; do not freeze; protect from light; use immediately after reconstitution or opening + + +In trials conducted elsewhere, both vaccines have shown 85-98% efficacy against severe rotavirus gastroenteritis and have been demonstrated to be safe with no increased risk of intussusception as compared to placebo. Simul­ taneous administration of rotavirus vaccines with OPV does not appear to affect adversely the efficacy of either vaccine. While efficacy trials in developing countries of Africa and Asia are ongoing, evidence suggests that the efficacy of the vaccine may be lower in countries with high rates of infection and competition for intestinal infection by other pathogens. However, the morbidity and mortality burden of rotavirus in countries like India is huge and routine immunization with current rotaviral vaccines, despite their lower efficacy in these settings, are expected to prevent significant morbidity and mortality. Hence the WHO and IAP endorse routine imminuzation with these vaccines while more efficacious and region specific vaccines are developed. +It is important to adhere to the vaccination schedule. Due to a small risk of intussusception, and the highest risk of rotaviral infections being in early infancy, it is recommended that immunization with current vaccines should be completed by the age of 8 months. Vaccination should be postponed in infants with acute gastroenteritis as it might compromise efficacy of the vaccine. Risks versus benefits of vaccination should be considered while considering vaccination for infants with theoretically increased risk of intussusception, such as chronic gastrointestinal disease and gut malformations. + +Haemophilus influenza B Vaccine +Worldwide, Haenwphilus influenza b (Hib) is an important cause of invasive infections like pneumonia, meningitis and bacteremia, especially in children below 2 yr of age. Effective vaccines are available and their incorporation into the immunization schedule of developed countries has resulted in a significant decline in morbidity and mortality attributable to invasive disease due to Hib. + +The capsular polysaccharide is the moiety used as the antigen in the available vaccines. Since polysaccharide antigens are poorly irnunogenic in children below 2 yr of age, it is conjugated to a protein antigen in order to enhance the immunogenicity. The PRP-T vaccine has the tetanus toxoid as the conjugate, the Hb-OC has the mutant CRM 197 diphtheria toxin, while PRP-OMP incorporates the outer membrane protein of meningococcus as conjugate. PRP-OMP is a more immunogenic vaccine than the other two. Conjugate vaccines for haemophilus influenza con­ taining diphtheria toxoid do not contain enough toxoid to be a substitute for DTP or DT. +The IAP-COI recommends that Hib vaccine be adminis­ tered to all children; however, given the epidemiological profile of infections with Hib, unirnmunized children above 5 yr of age should not receive the vaccine. Vacci­ nation is particularly recommended prior to splenectomy and in patients with sickle cell disease. Vaccination schedule depends on the age of the child at the time immunization is initiated (Box 9.12). Thevaccineissafeand immunogenic and has a protective efficacy of over 95%. The vaccine has been recently introduced as a pentavalent vaccine in some states in India in the National Program. + +Pneumococcal Vaccine +Worldwide, S. pneumoniae is responsible for 15-50% of all episodes of community acquired pneumonia, 30-50% of all cases of acute otitis media and 50% of deaths due to pneumonia every year. Among 90 known serotypes of S. pneumoniae, 20 serotypes are responsible for 80% of invasive pneumococcal disease in all ages, while only 13 serotypes account for 75% of disease burden in young children. In India, it has been demonstrated that serotypes 1, 4, 5, 6, 7, 14 and 19 are the most prevalent serotypes causing invasive pneumococcal disease in children. Children below the age of 2 yr are at greatest risk for invasive pneumococcal disease. The risk for pneumococcal disease is increased in children with congenital immuno­ deficiency, HIV, those on immunosuppressive therapy, + +Box 9.12: Haemophilus influenzae b vaccine Dose, route 0.5 ml intramuscular +Site Anterolateral thigh Schedule +National Program Introduced in some states as pentavalent vaccine with DPT and hepatitis B +IAP 2012 Three doses at ?.6 weeks given ?.4 weeks apart; one booster at 15-18 mo +Catch up At 6-12 mo: Two doses ?.8 weeks apart with one booster at 15-18 mo; At 12-15 mo: one dose and one booster at +15-18 mo; 15-60 mo: one dose; not recommended >5-yr-old +Adverse reactions Fever, rash, local pain or redness Contraindication Hypersensitivity to previous dose Storage 2-8°C +_ e_s_es_nt__i_P_edt_r_c __________________________________ +i +_ +_s +i +a +i +a +_ + + +organ transplant recipients, sickle cell disease, asplenia or hyposplenia, chronic cardiac, liver or pulmonary disease (excluding asthma unless on high dose oral steroids), chronic renal failure, nephrotic syndrome, diabetes mellitus and children with cerebrospinal fistula or cochlear implants. Currently, vaccines of two kinds are available, unconjugated polysaccharide vaccine and conjugated vaccines. +The unconjugated polysaccharide vaccine is a 23 valent vaccine (PPV23) containing 25 µg of polysaccharide of each of 23 serotypes contained in vaccine. Since capsular polysaccharides stimulate B cells directly independent of T cell stimulation, the vaccine is poorly immunogenic +below 2 yr and immunological memory is low. The vaccine does not reduce nasopharyngeal carriage of S. pneumoniae; +therefore, it does not provide herd immunity. Its efficacy in preventing invasive pneurnococcal disease in the high­ risk population is less than 70%. The vaccine is adminis­ tered intramuscularly in a dose of 0.5 ml; more than two life time doses should not be given. +Pneurnococcal conjugate vaccine (PCV) is available as a 13-valent polysachharide vaccine (PCV13) linked to a +protein carrier and a 10-valent conjugate vaccine (PCVlO) combined with non-typeable Haemophilus influenzae +vaccine. The introduction of conjugated vaccines for routine immunization in developed nations was asso­ +ciated with a herd effect, resulting from reduction in naso­ pharyngeal carriage of S. pneumoniae, causing a significant +decline in pneurnococcal disease in unvaccinated contacts of the vaccines. The antigens in the 13-valent conjugate vaccine are from serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F and 23F that account for the majority of invasive pneumococcal disease in children. The vaccine has a protective efficacy of 95-99% against invasive pneumococcal disease caused by these serotypes. The current vaccines replace the previously available PCV7 vaccine, which covered only 55% of pneurnococcal sero­ types prevalent in India. Conjugated vaccines with broader serotype vaccines should be available in future. +Since pneurnococcus is a cause of significant morbidity and mortality in children (especially below 2-yr-old), the IAPCOI recommends the use of the currently available conjugate pneumococcal vaccine (PCV13 or PCVlO) in healthy children aged <2 yr (Box 9.13). Revaccination or further doses after age appropriate primary series with PCV 13 is not currently recommended. Vaccination of healthy children >5 yr is likely to be associated with less benefits due to the low risk of invasive pneumococcal disease in these children and is not recommended. +All children at high-risk of acquiring the infection or at risk of complications should additionally receive the polysaccharide vaccine, because while PCV provides robust immune response and immune memory, PPV23 provides expanded serotype coverage. Where the cost of PCV is prohibitive, PPV23 alone is given to high-risk +children >2 yr of age. If affordable, PCV should be given + + +Box 9.13: Pneumococcal conjugate vaccines +Dose, route 0.5 ml subcutaneous or intramuscular Site Anterolateral thigh +Schedule +National Program Not included +IAP 2012 Three doses at -_6 weeks given -_4 weeks apart and one booster at 15-18 mo1•2 +Catch up At 7-11 mo: Two doses -_4 weeks apart and one booster at 15-18 mo; 12-23 mo: Two doses -_8 weeks apart; 2--59 mo: one dose; >60 mo: one dose, only if in high­ risk category +Adverse reactions Fever, local pain, soreness, malaise +Contraindication Anaphylaxis after previous dose Storage 2-8°C; do not freeze +1If primary immunization was with the 7-valent vaccine, administer one dose of the 13-valent vaccine to (i) children 14-59-mo-old; (ii) children 60-71-mo-old and an underlying medical condition. +2Children in high-risk categories should additionally receive the polysaccharide vaccine ?.8 weeks after the last dose of PCV vaccine.at at 2 yr of age; revaccinate with polysaccharide after 3--5 yr if continue to be at high-risk of infections + +first, in the schedule described above; for children over 5 yr a single dose of PCV is recommended. In children aged >2 yr, PPV23 should is given as a single dose. Only one additional dose of PPV23 is recommended in high-risk children; this may be given after 3-5 yr if the child is less than 10 yr of age and after 5 yr if child is aged more than 10 yr. + +Human Papillomavirus (HPV) Vaccine +Cervical cancer is the second most common cancer and the leading cause of cancer related deaths in women. The cancer is almost always caused by persistent infection with oncogenic human papillomavirus (HPV) belonging to 20 of 100 known serotypes of HPV. Serotypes 16 and 18 are associated with 70% cases of invasive cervical cancer. Oncogenic serotypes of HPV may also cause anal, vulvar, vaginal, penile and oropharyngeal cancers. Nononcogenic HPV serotypes 6 and 11 cause 90% of anogenital warts. +The available vaccines against HPV are self-assembling virus like particles (VLP) constituted of recombinant Ll, the major capsid protein of HPV. Since these do not contain any nucleic acid, these empty capsids are noninfectious but capable of eliciting a host immune response. VLP based vaccines prevent more than 90% new infections with the serotypes included in the vaccines. The vaccines do not protect against serotypes with which infection has already occurred before vaccination. +Two vaccines are currently licensed. Gardasil (HPV4) is a quadrivalent vaccine active against HPV strains 6, 11, 16 and 18 and Cervarix (HPV2) is a bivalent vaccine targeting only HPV 16 and 18. Clinical trials with both +vaccines have shown good efficacy against types 16, 18 related cervical in situ neoplasia grades 2 and 3 and +Immunization and Immunodeficiency - + + +adenocarcinoma in situ. Gardasil is also effective in preventing vaccine type related genital warts, vaginal intraepithelial neoplasia and vulvar intraepithelial neoplasia. Both vaccines are highly immunogenic and persistent protection for up to 5 yr has been demonstrated. There are no serious adverse events associated with HPV immunization. +The vaccine is of public health importance in a country like India where compliance with routine screening for cervical cancer is low and several women are diagnosed with the cancer every year. However, the duration of protection provided and hence, the ideal age at vaccination and need of booster doses, if any, remain to be determined. The vaccine is not expected to be effective in women already persistently infected with the virus. Any cross protection against other strains is likely to be modest. Sociocultural issues related to the vaccine being protective against a sexually transmitted disease may limit its acceptability. Importantly, immunization status should not create a false complacency resulting in a decline in routine screening for cervical cancer, especially when routine immunization has not been ensured, because this may result in a paradoxical rise in cervical cancer related mortality. Screening programs should therefore continue as per recommendations. +The IAPCOI recommends that the HPV vaccines should be offered to all girls who can afford the vaccine, given prior to sexual debut, as a cervical cancer preventing vaccine and not as a vaccine against a sexually transmitted infection (STI). The recommended age for initiation of vaccination is 10-12 yr, with catch up vaccination permitted up to 26 yr of age (Box 9.14). Both vaccines are contraindicated in +patients with history of hypersensitivity to any vaccine and +should be avoided in pregnancy. The vaccines may have a lower rnunogenicity and eficacy in rnunocomprosed hosts. At present boosters are not recommended. + +Japanese B Encephalitis Vaccine +Japanese encephalitis is an important cause of viral encephalitis in our country; being responsible for 2000- + + +Box 9.14: Human papillomavirus vaccine Dose, route 0.5 ml intramuscular +Site Upper arm (deltoid) Schedule +National Program Not included +IAP 2012 Girls 11-12 yr old (minimum 9 yr*) +HPV4: At 0, 2 and 6 mo; HPV2: 0, 1 and 6 mo) +Catch up Before initiation of sexual activity Adverse reactions Local pain, swelling, erythema; fever Contraindication Anaphylaxis after previous dose Storage 2-8°C; protect from light +* HPV4 may be given to boys as well + + +3000 cases and 500-600 deaths annually. In absence of specific therapy, vaccination remains the most important control measure and is indicated in all children between 1-15 yr of age residing in highly endemic areas like Andhra Pradesh, Uttar Pradesh and Karnataka. It should also be given to visitors to endemic areas if duration of stay is expected to be more than 4 weeks. Three types of vaccine are available, the mouse brain-derived inactivated vaccine, the cell culture-derived inactivated vaccine and the cell culture-derived live attenuated vaccine. +The mouse brain-derived vaccine is an inactivated vaccine administered subcutaneously in a dose of 0.5 ml for children between 1-3 yr and 1 ml in an older child. Primary immunization consists of 3 doses; the second and third doses are given 7 and 30 days after the first dose. Booster doses are administered at 1 yr after primary immunization and every 3 yr subsequently. Common adverse events include fever, malaise and local tenderness and redness. Reports of a temporal relationship of vaccination to acute encephalitis and anaphylactic reactions in recipients have resulted in decline in usage of this vaccine. An inactivated vaccine derived from primary hamster kidney cell line was popular in China, but its use was discontinued following availability of the live cell culture derived vaccine. +The cell culture derived live attenuated vaccine is the preferred vaccine in India. The vaccine is based on a stable neuro-attenuated strain of JE virus, the SA-14-14-2, and was first used in China and subsequently elsewhere in Asia. Studies demonstrate that the protective efficacy of on dose of the vaccine is 98-99% (Box 9.15). The vaccine has been used since 2006 in campaigns in hyperendemic districts of Uttar Pradesh, West Bengal, Assam and Karnataka. + +Influenza Vaccines +The influenza virus has three antigenic types (A, B and C) and several subtypes (based on the surface antigens hemagglutinin and neuraminidase), with frequent mutations due to antigenic drifts and antigenic shifts, resulting in frequent changes in the strains in circulation. Since the available vaccines elicit a strain specific hurnoral immune response, this is the only vaccine whose + + +Box 9.15: Japanese B encephalitis vaccine +Dose, route 0.5 ml subcutaneous +Site Anterolateral thigh or upper arm Schedule +National Program Only in endemic areas; one dose at 9 mo (minimum age 8 mo) +IAP 2012 Only in endemic areas +Catch up One dose in susceptible children up to 15-yr-old (during disease outbreak or in campaign) +Adverse reactions Fever, malaise +_ E_s_es_n__t__P_ed_r__s _________________________________ _ +i +i +at +i +a_i +c +_ + + +composition has to be altered yearly according to the expectation of the prevalent strain in the next peak season. Influenza vaccines are inactivated vaccines derived from viruses grown in embryonated hen's eggs and are of three types. Whole virus vaccines that were available previously were associated with significant adverse effects, especially in children; hence they are no longer used. Split product vaccines are produced from detergent treated highly purified influenza viruses. Surface antigen vaccines are subunit vaccines containing the purified antigens hem­ agglutinin and neuraminidase. Current vaccines are highly immunogenic and associated with minimal adverse events. The vaccines are usually trivalent, containing two influenza A subtypes and one influenza B strain. The composition of the vaccine is reviewed by the WHO six­ monthly to update antigens contained in the vaccine based on the prevalent circulating strains. The vaccine is recommended for use in high-risk children, including those with chronic cardiac or pulmonary disease, immuno­ deficiency, HIV infection, sickle cell disease, diabetes mellitus, systemic lupus erythematosus, longterm aspirin therapy and children with severe asthma who require oral corticosteroids. Recommendations for administration are +listed in Box 9.16. + +Meningococcal Vaccine +Neisseria meningitidis is a major ca use of bacterial meningitis accounting for 30-40% of cases in children below 15 yr. Endemic cases and severe meningococcal disease are primarily seen in children and adolescents; attack rates are highest in infants between 3 and 12 months of age. Even with treatment, case fatality rates are high (5-15%). The infection is usually due to serogroups A, B, C, Y and W135; serogroup A (and sometimes C) may cause epidemics. In India endemic cases are chiefly due to sero­ group B. Infection results in serogroup specific immunity. Two types of vaccines have been developed: the unconjugated polysaccharide vaccines and a conjugate group C vaccine. Unconjugated vaccines contain group specific capsular polysaccharides, which, like other polysaccharide vaccines, are T cell independent and do + +Box 9.16: Inactivated influenza vaccine +Dose, route 0.5 ml (0.25 ml <3 yr); intramuscular Site Anterolateral thigh or upper arm Schedule +National Program Not included +!AP 2012 Only in high-risk categories +First time vaccination: Two doses �4 weeks apart if 6 mo to 9-yr-old and one dose if >9 yr; annual revaccination with one dose; best administered before rainy season +Adverse reactions Local pain, redness; anaphylaxis +Contraindication Anaphylaxis after previous dose Storage 2-8°C; do not freeze + +not induce immunological memory and are not very immunogenic below 2 yr of age. Bivalent (containing group A and C) and tetravalent (containing groups A, C, Y and W135) vaccines are available. +The meningococcal vaccine is indicated in close contacts of patients with meningococcal disease (as an adjunct to chemoprophylaxis), certain high-risk groups (complement deficiency, sickle cell anemia, asplenia, before splenec­ tomy), during disease outbreaks (when caused by a serogroup included in the vaccine) and before travel to the high endemicity belt in Africa. +The vaccine is administered as indicated in Box 9.17. If required, revaccination is considered after 3-5 yr. The vaccine is not recommended for universal immunization in India. During epidemics, children above 2 yr of age may be administered the vaccine, particularly close household contacts. +The conjugated group C vaccine has been marketed in some countries where group C is the most common isolate in meningococcal disease. Three doses of the vaccine are administered 4-8 weeks apart in children below 6 months, while 2 doses suffice for 6-12 months age and 1 dose is enough in older children. + +Box 9.17: Meningococcal vaccine +Dose, route 0.5 ml subcutaneous or intramuscular Site Anterolateral thigh or upper arm Schedule +National Program Not included +IAP 2012 Single dose in high-risk categories older than 2 yr; repeat after 3-5 yr if required +Adverse reactions Fever, local pain or redness Contraindication Anaphylaxis after previous dose +Storage 2-8°C; protect from light; use within 30 min of reconstitution + +Rabies Vaccine +Rabies is endemic in India, accounting for 50% of global mortality associated with the disease. The previously available nerve tissue vaccines are no longer recommended due to poor efficacy and high incidence of adverse effects, like neuroparalytic reactions. Three types of vaccines are available against the virus. The purified duck embryo vaccine (PDEV), available for several decades, is free from myelin basic protein, is safe and its immunogenicity is comparable to modern tissue culture vaccines. Modern tissue culture vaccines include purified chick embryo cell (PCEC) vaccine (Rabipur), human diploid cell vaccine (HDCV) (Rabivax) and purified vero cell vaccine (PVRV) (Verorab, Abhayrab); these vaccines have similar efficacy and safety. The vaccines are available as lyophilized products that are reconstituted before use. The WHO requires each cell culture vaccine to have a potency of at least 2.5 IU per intramuscular dose. +Following an animal bite, the wound should be immediately irrigated with running water for 10 min, +Immunization and Immunodeficiency - + + + +cleaned thoroughly with soap and coated with povidone iodine, 70% alcohol or tincture iodine. All patients with wound category III (WHO recommendations) should receive rabies immunoglobulin (RIG), including trans­ dermal bites or scratches and contamination of mucous membranes with saliva (e.g. licks). RIG is not required in case of licks on intact or broken skin, nibbling of uncovered skin and minor scratches or abrasions without bleeding. Wound suturing should be avoided; if essential, suturing is postponed till after administration of RIG. +RIG provides passive immunity by neutralizing the rabies viruses, thus preventing neural infection. The dose of RIG is 20 U /kg for human (HRIG) and 40 U /kg for equine (ERIG) immunoglobulin. RIG should be infiltrated in and around the wound; in case of large or multiple wounds, RIG may be diluted with normal saline so as to infiltrate all wounded areas. Any remaining immuno­ globulin is administered intramuscularly at a site away from vaccine site, usually the deltoid or anterolateral thigh. HRIG is expensive and not widely available. ERIG is associated with a high-risk of adverse effects including anaphylaxis, and requires skin testing prior to its use. +The victim should receive postexposure prophylaxis with rabies vaccine by the intramuscular and intradermal route. The anterolateral thigh and deltoid region are pre­ ferred sites for intramuscular administration; the gluteal region should not be used. The dose is 1 ml for all modern tissue culture vaccines except PVRV in which case the dose is 0.5 ml. The intradermal dose is one-fifth of the intra­ muscular dose. Local pain, swelling or induration are common; less commonly, systemic symptoms may be noted, such as fever, malaise, abdominal pain or headache. The most commonly used schedule for administration is the Essen Schedule or WHO Standard Schedule, in which the vaccine is administered intramuscularly on days 0, 3, 7, 14 and 30. An additional dose on day 90 is recommended in immunocompromised or severely malnourished individuals. The Zagreb Schedule (two doses on day 0, a dose each on days 7 and 14) induces an early immune response, is now approved for use in India, using either PCEC or PRY, in centers with adequate training and frequent use of the vaccine. "The Thai red Cross Schedule involves administration of two intradermal doses each on days 0, 3 and 7 and one dose each on days 28 and 90. +Pre-exposure prophylaxis is offered to individuals at high-risk of rabies due to contact with animals, e.g. veterinary doctors, wildlife workers, dog handlers, taxidermists, postmen, animal laboratory workers, municipal workers, etc. Three doses are recommended to be given intramuscularly on days 0, 7 and 21 or 28. A booster dose is required after 1 yr and every 5 yr thereafter. In case of re-exposure after completed pre or post-exposure prophylaxis, two doses are recommended on days O and 3. The intradermal schedule using MTCV is also acceptable; here the boosters are required yearly. Since HRIG is required in addition to the vaccine for most animal bites + +and the availability, cost and knowledge regarding use of HRIG is limited, pre-exposure prophylaxis against rabies should be offered to all children at high-risk for rabies. + +Combination Vaccines +With the availability of vaccines against several diseases, a child needs to be administered more than twenty antigens in the first two years. A combination vaccine consists of multiple immunogens physically combined in a single preparation, including antigens or serotypes of the same pathogen (e.g. trivalent polio vaccine) or different pathogens (e.g. DTP vaccine). The concept is distinct from simultaneous administration of multiple physically separate vaccines at the same time at separate sites or by different routes. Studies indicate that the immune system of an infant can respond to a large number of antigens simultaneously, and that the efficacy of currently recommended vaccines is not altered by their concurrent administration, if recommended to be given at the same age. Combining vaccines has several benefits. The number of injections at each visit is decreased and fewer visits are required, leading to increased compliance and enhanced immunization coverage. Benefits to the immunization program include decreased requirement of storage space, decreased expenditure on packaging and transportation, and simultaneous vaccination against several diseases for children who have missed previous doses. +However, there are several challenges in the develop­ ment of combination vaccines. The antigens combined together in a vaccine should be compatible with each other, should not interfere with each other's immunological 'take' (relevant especially for live viral vaccines) and should be indicated at the same time. Some antigens may require an adjuvant to be present in the combination. The total volume of the vaccine should not be excessive and the product should be stable for at least 18-24 months. Before recommending a particular combination vaccine, its efficacy is evaluated in clinical trials and cost benefit analyses. Combination vaccines in common use include DTwP, DTaP, DT, dT, OPV, IPV, MMR and influenza vaccines. Other trivalent, quadrivalent or tetravalent combination vaccines that are available in India and abroad are listed in Table 9.6. Some vaccines are not available as combination vaccines but may be combined in the same syringe of permitted by the manufacturer, as indicated in the table. + +VACCINE ADMINISTRATION +Standard precautions should be followed to mize the risks of spreading infections during the administration of vaccines, including attention to hand washing, safe disposal of needles and vaccine vials and appropriate management of needle stick injury. Vaccine administrators should inspect the vaccine and diluent vials for the date of expiry, storage conditions and appearance. +_ Ess_e_tn__i__r _aP__idea__t_r_ic_ -------------------------------- +s +-- +_ +_ +_ + + + +Vaccine +dTaP +DTaP-Hib-IPV DTwP +DTwP-HB DTwP-HB-Hib + +DTaP-Hib DTwP-Hib HepA-HB Meningococcal Pneumococcal + +Table 9.6: Combination vaccines for use in children and infants Example +Boostrix®, Adacel® Pentaxim® +Multiple brands, e.g.Tripvac®, Triple antigen®, Comvac3® +® +® ® +Multiple brands, e.g. Shantetra , Q-VAC®, Tritanrix-HB , Tripvac-HB , Comvac-4-HB® Multiple brands, e.g. Easy-5 , Pentavac , Comvac-5 , Shan-5® +® +® +® +May combine vaccines if permitted by manufacturer, e.g. Qvac®+HibPro®, Hiberix®+ Tratanrix® May combine Tripacel®+ActHib®, Infanrix®+Hiberix® +® +® +Multiple brands, e.g. Easy-4®, Quadrovax , Shan-4 , TetractHib®; Triple antigen®+HibPro® Twinrix® +A, C, Y and 135 (Mencevax ACWY®); A, C, Y and 135 DT conjugate (Meningococcal A & C®) 7 valent (Prevnar®), 23 valent (Pneumo23®), polyvalent polysaccharide (Pneumovax®) + +Combination vaccines licensed elsewhere but not in India (common brands) +DTaP-HB (Tritanrix®), DTaP-HB-IPV (Pediatrix®), DTaP-HB-IPV /Hib (Infanrix hexa®), dT-IPV, DTaP-IPV (Quadracel®) Hib--HB (Comvax), Hib-DT (Vaxem HIB®), Hib-TT conjugate (ActHIB®), Trivalent Hib type A, B, split virion (Vaxigrip®) HepA-Typhoid (Hepatyrix®); MR + varicella (Priorix tetra , Proquad®) +® +Combined ACW135Y polysaccharide meningitis (ACWY Vax®) + + +Vaccines available as lyophilized powder may require to be reconstituted in (i) sterile or distilled water, e.g. vaccines against measles, mumps, rubella (with or without varicella), meningococcus (MPSV4), rabies (HDCV, PCECV), varicella or zoster; (ii) normal saline, e.g. Hib vaccine; or (iii) another vaccine, e.g. combination vaccines combining DTaP, polio and Hib vaccines (the diluent contains the DTaP-IPV vaccine) and tetravalent meningo­ coccal vaccine (the diluent contains MenCWY vaccine). The maximum time allowed between reconstitution and use varies from within 30 min (DTaP-IPV-Hib, MMRV, Hib with MenCY, rabies, varicella and zoster), to 8 hr (MMR, MCV4) or 24 hr (Hib, rotavirus vaccines). The reconstituted vaccine should not be used if there is discolo­ ration, extraneous particulate matter and obvious lack of resuspension of the lyophilized powder. +Anxiety and pain are commonly associated with vaccination. Some evidence-based strategies used to reduce these include: (i) the use of antipyretics to ease pain; (ii) age-appropriate nonpharmacologic distraction techniques (reading books, playing music, pretending to blow away the pain, deep breathing); (iii) breastfeeding or ingestion of sweet-tasting liquids before or during vaccination; (iv) aistering the most pul vaccine (e.g. MMR, PCV or HPV) last; (v) stroking the skin near the injection site; (vi) administering intramuscular injections rapidly without aspiration; and (vii) the use of topical analgesia (e.g. 5% lidocaine or prilocaine emulsion or spray). Other techniques that may lessen anxiety in older children are explaining the procedure, and administering the vaccine in the sitting position rather than lying down. + +Adverse Events following Vaccination +An adverse event following immunization is any untoward effect observed after vaccination, and may be categorized as follows: (i) Vaccine-induced: Event is caused by the + + +vaccine or the individual's response to its administration, and would not have occurred without vaccination, e.g. vaccine-associated paralytic poliomyelitis, BCG related adenitis or encephalopathy following DPT; (ii) Vaccine­ potentiated: Events that are precipitated by vaccination but may have occurred without vaccination, e.g. the first febrile seizure in a predisposed child; (iii) Programmatic error: An event caused by technical error in vaccine preparation, handling or administration, e.g. toxic shock syndrome due to bacterial contamination of measles vaccine; and (iv) Coincidental: An event that is temporally linked to the vaccination but is expected to have followed vaccine administration only by chance or due to unrelated illness. Common events following vaccination include fever, irritability and swelling and redness at the injection site. These are self limiting or may require the use of cool compresses or paracetamol. Immediate-type allergic reactions to vaccines are rare and dficult to predict. Severe reactions (e.g. anaphylaxis) are usually IgE mediated, occur in response to vaccine constituents (rather than microbial contamination) and usually appear within minutes. While anaphylaxis may follow admnistration of any vaccine, the most commonly implicated are the vaccines against yellow fever, MMR and tetanus. Since symptoms may sometimes be delayed, each child should be observed for at least 15 min after vaccine administration. It is important to distinguish anaphylaxis from vasovagal reaction following vaccination. Prior history of syncope with painful stimuli and the presence of pallor and bradycardia, rather than flushing and tachycardia (seen with anaphylaxis) suggest syncope +rather than anaphylaxis. +When evaluating for a possible vaccine allergy, one should consider the timing of reaction and history of previous exposure to the vaccine. If a repeat dose of the same or similar vaccine is considered necessary, the child should be evaluated by a dermatologist for the need for a +Immunization and Immunodeficiency - + + + +skin test. Components of vaccines implicated in mediating allergic reactions include (i) Egg protein: yellow fever (skin test mandatory; may also contain chicken protein), measles, MMR, rabies PCEV, influenza killed injectable and live attenuated vaccines; (ii) gelatin: influenza, measles, MMR, rabies, varicella, yellow fever and zoster vaccines; (iii) latex in the rubber of the vaccine vial stopper or syringe plunger; (iv) casein: DTaP vaccine; and (v) Saccharomyces cerevisiae yeast: hepatitis B and human papillomavirus vaccines. Antimicrobials added to vaccines in traces (e.g. neomycin) rarely cause allergic reactions. Thimerosal, aluminum and phenoxyethanol, added to some vaccines as preservatives, may cause +delayed type hypersensitivity or contact dermatitis. The +use of thimerosal has declined due to concerns over mercury exposure. Rare delayed reactions are erythema nodosum and encephalopathy. +Reportable events following vaccination include: (i) anaphylaxis or anaphylactic shock s7 days of any vaccine; (ii) adverse effects listed as contraindications to future vaccination in the package insert; (iii) any serious or unusual event; and (iv) any sequelae of reportable events. Vaccine-specific reportable events include: (i) oral polio: paralytic polio or vaccine-strain polio within 1-6 months of vaccine administration; (ii) measles: thrombocytopenic purpura within 7-30 days; measles infection by vaccine strain in an immunodeficient recipient s6 months of vaccination; (iii) measles, mumps and/ or rubella: encephalopathy or encephalitis <15 days; (iv) tetanus: brachial neuritis s28 days; (v) pertussis: encephalopathy or encephalitis s7 days; (vi) rotavirus: intussusception s30 days; and (vii) rubella: chronic arthritis <6 weeks. + +Vaccine Storage and Cold Chain +The cold chain is a system of storing and transporting vaccines at recommended temperatures from the point of manufacture to the point of use. Maintenance of appro­ priate temperature is critical to the viability and potency of a vaccine. Vaccines such as BCG (especially after reconstitution), OPV and measles are sensitive to heat but can be frozen without harm. In contrast, vaccines like OT, DPT, dT, hepatitis B and tetanus toxoid are less sensitive to heat and are damaged by freezing. Other vaccines that must not be frozen include hepatitis A, Hib and whole cell killed typhoid vaccine. In the refrigerator, OPV vials are stored in the freezer compartment (0 to -4°C). In the main compartment (4-10°C) BCG, measles and MMR are kept in the top rack (below the freezer); other vaccines like DPT, OT, TT, hepatitis A and typhoid are stored in the middle racks; while hepatitis B, varicella and diluents are stored in the lower racks. + +IMMUNIZATION PROGRAMS +The Expanded Program ofImmunization (EPI), introduced by the World Health Organization (WHO) in 1974, was the first global initiative at immunization and focused on vaccinating + + +young children and pregnant women. When adopted by India in 1978, the EPI included Bacillus Calmette Guerin (BCG), diphtheria and tetanus toxoids and whole cell pertussis (DTwP), oral poliomyelitis (OPV) and typhoid vaccines, and covered chiefly urban areas. The Universal Immunization Program (UIP) was introduced in 1985 to improve immunization coverage witin India and to extend its focus beyond infancy. Measles vaccine was added to the Program and typhoid vaccine excluded. Further, vitamin A supplementation was introduced in 1990 and Polio National Immunization Days were initiated in 1995. Under the UIP, some states have initiated universal immunization against hepatitis B virus since 2002. A pentavalent vaccine combining Haemophilus influenza b (Hib) and hepatitis B vaccines with diphtheria toxoid, whole cell pertussis and tetanus toxoid (DTwP) vaccines has been introduced in some states since 2011. The UlP has remained an essential part of the Child Survival and Safe Motherhood (CSSM) program in 1992, the Reproductive and Child Health (RCH) program I in 1997 and the RCH II and National Rural Health Mission (NRHM) since 2005. The efforts of UIP are also supported by Child Vaccine Initiative (CVI) and Global Alliance for Vaccines and Immunization (GAVI). +The proportion of 1-yr-old children immunized against measles is an important indicator for immunization coverage within the country. While the UIP achieved a significant decline in the incidence of vaccine preventable diseases, the findings of the National Family Health Survey 2005-2006 suggested that only 43.5% of children in India received all the primary vaccines by 12 months of age and this coverage was below 30% in Uttar Pradesh, Rajasthan and Arunachal Pradesh. The Immunization Strengthening Project of the Government of India was launched with the intent to: (i) strengthen routine immunization rates to increase the percentage of fully immunized children to above 80%; (ii) eliminate and eradicate polio; (iii) review and develop a new immunization program based on the availability of newer vaccines, recent advances in vaccine production and cold chain technologies and the changing epidemiology of diseases; and (iv) improve vaccination surveillance and monitoring. This program is being implemented through the National Institute of Health and Family Welfare and regional training centers. +Strengthening of immunization coverage is an important component of the NRHM. Measures proposed to improve vaccination rates include mobilization of children and pregnant women by Accredited Social Health Activist (ASHA) and link workers to increase coverage and decrease dropouts, provision of auto-disable syringes and other disposable and strengthening of cold chain maintenance and immunization monitoring systems. + +Recommendations of the Indian Academy of Pediatrics Committee on Immunization (IAPCOI) +The IAPCOI endorses the National Immunization Program, but recommends certain additional vaccines for +___ _s_s_ _n_t_iai_P_ed_iat_rics _________________________________ _ +E +e +_ +_ +_ +_ +_ + + +Indian view of data available on vaccine preventable dis­ +eases (VPDs) and the availability of several vaccines. These include the vaccines for hepatitis A, Haemophilus influenzae type b, MMR, typhoid, pneumococcal, varicella, HPV, and +rotavirus vaccine. The differences in the National Immuni­ zation Program and the recommendations of the IAP are highlighted in Table 9.7. + +IMMUNIZATION IN SPECIAL CIRCUMSTANCES + +The Indian Academy of Pediatrics also categorizes certain high-risk categories of children that need to be adminis- + +tered additional vaccines (Table 9.8). Some specific aspects are discussed here. +Lapsed immunization. Table 9.9 outlines suggested schedules for children who have missed routine immunization. The vaccination schedule for adolescents is discussed in Chapter 4. +Preterm neonates. Most preterm and low birth weight babies mount adequate immune responses, and should receive immunization at the same chronological age and according to the same schedule and precautions as for full term infants. The dose administered is as for other infants, + + + +Table 9. 7: Comparison of the vaccinations scheduled in the National Immunization Program and the 2012 recommendations of the Indian Academy of Pediatrics (IAP) + +Age +0 (at birth) 6 weeks 10 weeks 14 weeks 6 mo +9 mo 12 mo 15 mo +16-24 mo + +2 yr 5 yr 10 yr 16 yr + + +National Immunization Program +BCG, OPVO, HepBO* +DTwPl, OPVl, Hep Bl*,Hibl* DTwP2, OPV2, HepB2*,Hib2* DTwP3, OPV3, Hep B3*,Hib3* + +Measles, vitamin Al + +MMR* +DTwPBl, OPVBl, vitamin A26, Japanese encephalitis*• + +DTwPB2 TT +TT + +IAP recommendation +BCG, OPVO, HepBl +DTwPl/DTaPl, IPV1$, Hep B2, Hibl, Rotavirusl, PCVl DTwP2/DTaP2, IPV2$, Hib2, Rotavirus2, PCV2 DTwP3/DTaP3, IPV3$, Hib3, Rotavirus3, PCV3 OPVl/HepB3 +OPV2, Measles Hep Al +MMRl, Varicellal, PCVBl +(16-18 mo) DTwP Bl/DTaP Bl, IPVBl$, Hib Bl (18 mo) Hep A2 +Typhoidl** +DTwP B2/DTaP B2, OPV3, MMR2, Varicella2, Typhoid2 TdaP / Td$$, HPV + +Bl first booster dose; B2 second booster dose; BCG Bacillus Calrnette Guerin vaccine; OT diphtheria toxoid with tetanus toxoid; DTwP diphtheria toxoid, tetanus toxoid, whole cell killed pertussis vaccine; DTaP diphtheria toxoid, tetanus toxoid, acellular pertussis vaccine; Td tetanus toxoid with reduced dose diphtheria; Tdap tetanus toxoid with reduced dose diphtheria and pertussis vaccine; Hep B hepatitis B vaccine; Hib Haemophilus influenzae b vaccine; HPV human papillomavirus vaccine; MMR measles,mumps and rubella vaccine; OPV oral poliovirus vaccine; PCV pneumococcal conjugate vaccine; TT tetanus toxoid +* lrnplemented in selected states, districts and cities •• SA 14-14-2 vaccine, in select endemic districts +s OPV if a inactivated polio vaccine (IPV) is not afforded +ss dT preferred over TT + +Table 9.8: High-risk conditions in which certain vaccines may be necessary + +Circumstances that increase risk of acquiring certain infections +Congenital or acquired immunodeficiency (including HIV infection) Chronic cardiac, pulmonary•, hematologic, renal (including nephrotic +syndrome), liver disease and diabetes mellitus +Prolonged therapy with steroids, other rnunosuppressive agents Radiation therapy +Diabetes mellitus +Cerebrospinal fluid leak, cochlear implant Malignancies +Children with functional/ anatomic asplenia/hyposplenia During disease outbreaks +Laboratory personnel and health care workers Travelers + +Vaccines that may be necesssary +Influenza vaccine Meningococcal vaccine Japanese encephalitis vaccine Cholera vaccine +Rabies vaccine Yellow fever vaccine +Pneurnococcal polysaccharide vaccine (PPSV 23) + +Adapted from the recommendations of the Indian Academy of Pediatrics Committee on Immunization, 2012 *includes asthma if treated with prolonged high-dose oral corticosteroids +Immunization and Immunodeficiency - + + +Table 9.9: Vaccination of a previously unimmunized child + +Visit +Age �7 yr + + + +Age >7 yr + + +At evaluation +BCG1 +Oral poliovirus1 DTwP/DTaP Hepatitis B Tdap +Hepatitis B + + +After 1 mo +Oral polio virus 1 DTwP/DTaP Hepatitis B + +dT3 Hepatitis B + +After 2 mo +MMR (preferred) or measles Typhoid + + +MMR Typhoid + + +After 6 mo +DTwP/DTaP Hepatitis B + + +Hepatitis B + +1If age is <5-yr-old +2Repeat after ?.4 weeks if not received any doses previously 3Repeat every 10 yr +Adapted from the recommendations of the Indian Academy of Pediatrics Committee on Immunization, 2012 + + + +and use of divided or reduced doses is not recommended. Seroconversion rates following most live and killed vaccines are similar to full term babies, except for hepatitis B vaccine. Seroconversion rates are HBV vaccine are lower among preterm babies with birthweight below 2000 g. If the mother is known to be HBsAg negative, the first dose of the vaccine can be safely postponed to one month of age for such newborns. However, preterm low birth­ weight neonates born to HBsAg positive mothers or to those with unknown HBsAg status should receive both the HBV vaccine and hepatitis B immunoglobulin within 12 hr of birth for immediate protection. +Primary or secondary immunodeficiency Immunodeficiency may be primary or secondary to malignancy, HIV infection, steroids or other immunosuppressive therapy. Such children are at increased risk of infections with certain pathogens, and the severity of vaccine preventable diseases may be higher than in immunocompetent child­ ren. It is recommended that these children receive inactivated influenza and pneumococcal vaccines. Live viral or bacterial vaccines are usually contraindicated due to the risk of serious disseminated disease by the organism in the attenuated vaccine, e.g. with BCG, OPV, measles, MMR, oral typhoid and varicella vaccines. These patients may safely receive toxoid and killed vaccines. However, the vaccine efficacy may be compromised due to immune dysfunction, which may require testing for specific serum antibodies, and administration of further doses. Since household contacts of immunocompromised children may transmit OPV to the patient, IPV is preferred in siblings of immunodeficient children. +Therapy with corticosteroids at 2 mg/kg/ day or 20 mg per day of prednisolone or its equivalent is considered as significant immunosuppression during which live vaccines should not be given; killed or inactivated vaccines and toxoids are safe. Live vaccines may be administered if corticosteroids are given for less than 14 days, in lower doses, on alternate days or by inhaled, topical or intra­ articular routes. Vaccination with live vaccines may be resumed 4 weeks after stopping therapy with high dose corticosteroids. Wherever possible, vaccination should be + +completed prior to initiation of chemotherapy, immuno­ suppressive drugs or radiation. Live vaccines should not be given for at least 3 months after such treatment while inactivated vaccines given during such therapy might need to be repeated afterwards. +Children infected by HIV are susceptible to severe and/ or recurrent infections with usual or unusual pathogens. The efficacy and safety of vaccines in such children depends on the degree of immunodeficiency. Most vacci­ nes are safe and efficacious in early infancy as the immune functions are relatively intact, but the longevity of immune response may be affected as the disease advances, The efficacy and safety of vaccines are significantly decreased in advanced HIV disease. Vaccination of a baby born to an HIV positive mother but with an indeterminate HIV status should be as per the normal schedule. Symptomatic infants should not receive BCG vaccine. Measles, MMR and varicella vaccines may be administered if the CD4 count is >15% for the age. Seroconversion should be documented following hepatitis A and hepatitis B immunization; four doses may be required in double doses for achieving seroconversion against hepatitis B. +Splenectomy. Children with splenectomy or anatomical or functional asplenia (e.g. sickle cell disease) are at an increased risk of infections with encapsulated organisms (e.g. S. pneumoniae, N. meningitidis, H. influenzae b). Where possible, vaccines against these organisms should be considered at least two weeks before elective splenectomy. + +Passive Immunization +Passive immunity is resistance based on antibodies preformed in another host. Preformed antibodies to cer­ tain viruses (e.g. varicella, hepatitis B) can be injected during the incubation period to limit viral multiplication. Nonspecific normal human immunoglobulin serves the same purpose when specific immunoglobulin is not available, e.g. to protect from hepatitis A or measles. Passive-active immunity involves giving both preformed antibodies immune globulins to provide immediate protection and a vaccine to provide longterm protection, e.g. in preventing tetanus and hepatitis B. These pre- +__ _s_s_ _n_t_ia1_P_ed_iat_rics __________________________________ +E +e +_ +_ +_ +_ +_ + +Table 9.1 O: Passive immunization Infection Target population Dose* Normal human immunoglobulin + +Hepatitis A + +Measles + +Institutional outbreak; unimmmunized contact of infected individual; travel to endemic area +Immunocompromised person or an infant <1-yr-old exposed to infected person <6 days back + + +0.02 ml/kg (3.2 mg/kg); repeat every 4 mo if travel is prolonged +0.5 ml/kg (immunocompromised individual); 0.25 ml/kg (infant) + +Specific (hyperimmune globulin) + +Hepatitis B + + +Varicella + + +Rabies Tetanus + +Newborn of HBsAg positive mother 0.5 ml (> 100 IU) within 24 hr of birth Percutaneous or mucosal exposure; sexual contact 0.06 ml/kg (32-48 JU/kg; maximum 2000 IU) +within 7 days (preferably 48 hr) of exposure Newborn of infected mother with lesions noted 5.6 12.5 (5-25) U/kg (maximum 625 units) +days of birth; infant <1-yr-old or immunocompromised child exposed to infected person <6 days back +Bite by rabid animal 20 units/kg +Wound/exposure in unimmunized or incompletely 250 units for prevention; 3000-6000 units for immunized individual; treatment of tetanus therapy + +Antisera/Antitoxin + +Diphtheria antitoxin +Anti-tetanus serum (horse) +Rabies antiserum + +Susceptible contact + +Wound/exposure in unimmunized or incompletely immunized individual +Bite by rabid animal + +500-1000 units + +1500 units subcutaneous or intramuscular + +40 IU/kg + +*Administered intramuscularly unless specified + + +parations should be given at different sites in the body to prevent the antibodies from neutralizing then immuno­ gens in the vaccine. Administration of antibody against diphtheria or tetanus allows large amounts of antitoxin to be immediately available to the host to neutralize the toxins. Table 9.10 tabulates common indications in which +passive immunization provides protection from disease. + +Suggested reading +Indian Academy of Pediatrics Committee on Immunization (IAPCOI). Consensus Recommendations on Immunization and IAP Immunization Timetable 2012. Indian Pediatr 2012;49: 549-64. +www.iapcoi.com/hp/pdf/IAPCOI www.aapredbook.aappublications.org/site/resources www.immunize.org/catg.d/p3040.pdf www.aap.org/immunization/IZSchedule.hrnl +- Essential Pediatrics + + + +unknown. However, fever may also be associated with adverse effects, such as increased insensible water losses, cardiopulmonary stress, paradoxical suppression of immune response and triggering of febrile seizures in predisposed patients. Reduction of fever is essential in patients with past or family history of febrile seizures and patients with critically illness, cardiorespiratory failure, disturbed fluid and electrolyte balance and those with temperature exceeding 40°C (104°F). Treatment should be individualized in other patients and parental counseling is important. +The two antipyretic drugs commonly used in children are paracetamol and ibuprofen. Other agents such as aspirin, nimesulide and mefenamic acid are associated with high incidence of adverse effects and are better avoided. Therapy with ibuprofen decreases fever at the same rate as paracetamol, but therapy with ibuprofen shows a slightly lower nadir and prolonged duration of action (6 hr) as compared to paracetamol (4 hr). However, the risk of side effects such as acute renal failure and gastrointestinal bleeding is theoretically higher with ibuprofen. Conversely, the consequences of overdose with paracetamol (hepatic failure) are more sinister than those with ibuprofen (renal failure, neurological depression). Considering all factors, it is reasonable to use paracetamol at a dose of 15 mg/kg every 4 hr (maximum 5-6 doses/ day) as the first-line drug for fever management. Patients who have not adequately responded to paracetamol may receive ibuprofen at a dose of 10 mg/kg every 6 hr. There is marginal benefit on amelioration of fever by combining paracetamol and ibuprofen as compared to using either drug alone without increase in toxicity. Tepid water sponging may be used as a complementary method to drug therapy in bringing down fever quickly. +Heat illness is a medical emergency. High temperatures can cause irreversible organ damage and should be brought down quickly. Since the hypothalamic set point is not altered, nonsteroidal anti-inflammatory drugs, which act by reducing prostaglandin production, are ineffective. External cooling with ice water sponging, cooling blankets, cold water enemas and gastric washes are helpful. Simultaneously, measures to correct the underlying condition are required. + +Suggested Reading +Crocetti M, Moghbeli N, Serwint J. Fever phobia revisited: Have parental misconceptions about fever changed in 20 yr? Pediatrics 2001;107:1241-6 +Sherman JM, Sood SK. Current challenges in the diagnosis and management of fever. Curr Opin Pediatr 2012;24(3):400-6 + +Short Duration Fevers +Short duration fever lasting for less than 5-7 days are among the most common reasons for pediatric outpatient visits. While the overwhelming majority are due to viral infections, fever without localizing signs or focus in children below the age of 3 yr (especially below 3 months) + +are of great concern as they may indicate a serious bactE infection. Since H. inl-uenzae and S. pneumoniae important causes of serious bacterial infection, ·, algorithms suggested below may change with increasi rates of immunization with H. inl-uenzae and S. pneumon vaccines. + +Fever without Focus in Newborns +Fever in a neonate is a medical emergency, since thei infants have 5-15% risk of serious bacterial infection sue as sepsis, bacteremia, urinary tract infections, pneumoni, enteritis and bacterial meningitis and may look we! despite carrying a serious infection, delaying the diagnosi: of sepsis. +Sometimes neonates develop fever due to over clothing or warm weather ('dehydration fever'). The baby looks well and active and only requires observation with frequent feeding and nursing in less warm environment. The infant is observed for signs of sepsis and, if diagnosis is doubtful, investigated. +A febrile neonate requires a detailed assessment (Fig. 10.1). A neonate with toxic appearance has high-risk of serious bacterial infections and should be treated aggressively. He/She should be admitted to undergo a complete sepsis evaluation. Therapy with antibiotics (third generation cephalosporins, e.g. cefotaxime or ceftriaxone, with or without an aminoglycoside) should be initiated while awaiting results of investigations. Supportive therapy is instituted, as required. The management of a well-appearing febrile neonate is controversial. For fever suspected to be due to overdressing, temperature assessment should be repeated 15-30 min after undressing. Most guidelines recommend hospitalization of well-appearing febrile infants below 1 month of age as they may have serious bacterial infection. These infants should undergo basic evaluation including blood counts and C reactive protein. Cultures should be sent if possible. Patients with positive septic screen should receive IV antibiotics after lumbar puncture and CSF examination. If the screen is negative, the baby is observed and a screen + +Fever >38°C in less than 90 days age, no focus +• +:i +Well looking Sick looking, - -, +.t - +r +- ++ + Screen Hospitalize +Blood counts, urinalysis CRP +Cultures: blood, urine, CSF +Normal screen +IV antibiotics +TLC 5000-15,000/mm3 +Band count normal Abnormal +CRP negative screen Repeat screen if needed ----+ observe until afebrile +Urinalysis normal + +Fig. 10.1: Evaluation of fever in a patient less than 3-month-old; CRP (-reactive protein; CSF cerebrospinal fluid; IV intravenous; TLC total leukocyte count +Infections and Infestations - + + + +repeated 6-12 hr later. If repeat screen is also negative, observation is continued till the baby is afebrile and culture reports are available. By then most babies would have either become afebrile or a focus would have developed. + +Fever without Focus in an Infant 7 -3-Month-Old +Similar to neonates, 10% infants in this age group may have serious bacterial disease, with 2-3% risk of bactere­ mia. Also, they may look well but still have bacteremia. The algorithm for management of these babies is similar to newborns (Fig. 10.1) and includes a detailed clinical assessment. As fever may relate to immunization, history must include that of recent vaccination. +Toxic or ill-appearing babies require management similar to sick febrile neonates. One to 3-month-old febrile infants who appears well should undergo a complete sepsis evaluation through the outpatient department including leukocyte and platelet counts, band cell count, C-reactive protein, urinalysis, urine and blood cultures and, if indicated, smear for malarial parasite, and chest X­ ray. CSF examination is undertaken if there is no clue to focus of infection. If the screen is positive, the patient is hospitalized and treated with antibiotics. A well-looking infant with no clinical focus of infection and a negative screen (leukocyte count <15,000 mm3, band count <20%, negative C-reactive protein, urine white cells <10/HPF) can be observed at home without antibiotics, provided the care takers are reliable and agree to bring the infant for reassessment 24 hr and 48 hr later. + +Fever without Focus in Children 3-36-Month-Old +The risk of serious bacterial infections decreases to 5% in this age group. Detailed history is taken about vaccination, history of sick contacts in the family and the condition of the child when fever is down. If the child looks toxic, he requires hospitalization and appropriate evaluation and treatment. In a nontoxic child with fever less than 39°C, one can merely observe. Children with fever more than 39°C have a high-risk of bacteremia and testing with leukocyte count and examination of smear for malarial parasite are recommended. If the leukocyte count is > 15,000/ mm3, blood culture should be sent and the patient administered IV ceftriaxone on either an inpatient or outpatient basis. A count below 5000 / mm3 suggests a viral +infection or enteric fever. If the count is below 15 000 mm3 observation is continued; if fever persists bey�nd 48 h; without development of a focus, evaluation should include complete blood counts, smear for malaria, urine microscopy and blood culture. + +Suggested Reading +Baker MD. Evaluation and management of infants with fever. Pediatr Clinics North Am 1999;46:1061-72 +Jhaveri R, Byington CL, Klein JO, Shapiro ED. Management of the non-toxic appearing acutely febrile child. J Pediatr 2011;159:181-5 +Section on clinical pharmacology and therapeutics. Fever and antipyretic use in children. Pediatrics 2011;127:530-7 + +Fever of Unknown Origin +Fever of unknown origin (FUO) is defined as fever > 101°C lasting for 3 weeks or more for which no cause is apparent after 1 week of outpatient investigation. A practical defi­ nition is fever > 101°F measured on several occasions over a 7-day period. + +Causes +The principal causes are listed in Table 10.1. Infections account for 60-70% cases in children. Most common infectious causes include enteric fever, malaria, pulmonary or extrapulmonary tuberculosis and urinary tract infections. The remaining cases are due to malignancies, chiefly leukemia and autoimmune diseases, chiefly juvenile rheumatoid arthritis. Uncommon causes include drug fever, temperature dysregulation, diabetes insipidus, sarcoidosis, ectodermal dysplasia and sensory autonomic neuropathies. Even with extensive investigations, the cause remains undiagnosed in 10-20% cases. + +Approach to Evaluation +The first step is to identify sick patients who need stabili­ zation and urgent referral. Subsequently, all attempts are made to identify the etiology. A detailed history is of para­ mount importance. This should include: (i) whether and how fever was documented (not uncommonly, children with history of prolonged fever do not have fever documented on a thermometer); (ii) duration and pattern of fever (to distinguish from recurrent fever); (iii) symptoms referable to various organ systems, weight loss; (iv) recurrent infections and/ or oral thrush (suggests HIV infection); (v) jointpain,rash, photosensitivity (autoimmune disease); (vi) contact with person with tuberculosis; animals (brucellosis); (vii) travel to endemic zones (kala-azar); and (viii) history of intake of anticholinergics (drug fever). +Complete physical examination should include documentation of fever, followed by assessment of general activity, nutrition and vital signs. Physical examination, including head to toe examination, should be repeated + + +Table 10.1: Causes of fever of unknown origin Infectious +Enteric fever, malaria, urinary tract infections, tuberculosis, chronic hepatitis, HIV, occult abscesses (liver, pelvic), mastoiditis, sinusitis, osteomyelitis, meningitis, infectious mononucleosis, infective endocarditis, brucellosis, CMV, toxoplasmosis, kala-azar +Autoimmune +Systemic onset juvenile rheumatoid arthritis, Kawasaki disease, systemic lupus erythematosus, inflammatory bowel disease, polyarteritis nodosa +Malignant +Leukemia, lymphoma, Langerhans cell histiocytosis +--E•s•s•e•n•t-ia•l•P• e•d-ia.t.ri•c• --------------------------------- +s +- + + +daily as new findings may emerge that provide a clue to the etiology. Kawasaki disease, though relatively uncom­ mon, must be kept in mind as diagnosing the illness before the tenth day of fever is crucial to prevent coronary complications (Figs 10.2A and B). + + + + + + + + + + +Figs 10.2A and B: Kawasaki disease: (A) Red and cracked lips; (B) palmar rash and swelling + +Preliminary investigations which should be done in all patients with FUO include complete blood counts, peri­ pheral smear, malarial parasite, erythrocyte sedimentation rate, blood culture, Widal, chest X-ray, tuberculin test, urinalysis and culture, hepatic aminotransaminases and abdominal ultrasound. Specialized investigations are based on clinical clues. +If the above approach yields a diagnosis, appropriate treatment should be instituted. Inability to make a specific diagnosis merits reassessment and further investigations. While second line investigations are planned, treatment with intravenous (IV) ceftriaxone may be initiated since enteric fever is an important cause of FUO in India, particularly in cases where preliminary investigations are noncontributory. +Second-line investigations include HIV ELISA, contrast enhanced CT of chest and abdomen, bone marrow smear, biopsy and cultures, 20 echocardiogram, complement C3 level, antinuclear antibody, rheumatoid factor and specific tissue biopsies, if indicated. Other serologic tests may include serology for brucellosis, HBsAg and Paul Bunnel test, Monospot test or IgM antibody to viral capsid antigen +for infectious mononucleosis. Tests of no clinical value include serology and PCR for M. tuberculosis. +It should be possible to determine the etiology of FUO in most cases. In a small number of cases, no cause is found. In such cases, periodic reassessment is useful as lymphoma or systemic onset juvenile rheumatoid arthritis may finally surface. Some cases are self limiting. Uncom­ monly, use of antitubercular therapy with four drugs for a month is advised in sick patients. Empirical use of corticosteroids should be avoided. + +Suggested Readng +i +Tolan RW. Fever of unknown origin: A diagnostic approach to this vexing problem. Clin pediatr 2010;49:207-13. + +Fever with Rash +Fever with rash is a common and vexing problem. It may signify serious disorders such as meningococcemia or dengue hemorrhagic fever or may be associated with minor drug allergy. The common infectious and non­ infectious causes of fever with rash are listed in Table 10.2. + +Evaluation +The nature of the rash often provides clues to determine the etiology of the exanthematous febrile illness (Fig. 10.3). Rashes may be macular, maculopapular, vesicular, nodular, urticaria! or purpuric (Table 10.2) and consi­ derable overlap may occur with varying presentations of the same etiology. Other factors that assist in diagnosis include epidemiological factors, season, history of exposure, incubation period, age, vaccination status, previous exantherns, prodromal symptoms, relation of rash with fever, distribution and progression of the rash, involvement of mucous membranes, drug intake and associated symptoms. + +Table 10.2: Common exanthematous illnesses in Indian children Macular or Maculopapular rash +Common: Measles, rubella, dengue, roseola infantum, erythema infectiosum, drug rash, adenoviral or enteroviral infections Less common: Infectious mononucleosis, chikungunya, HIV, +Mycoplasma pneumoniae, secondary syphilis, brucellosis, scrub typhus, chronic hepatitis B, cytomegalovirus, lupus, systemic onset juvenile rheumatoid arthritis +Diffuse erythema with peeling or desquamation +Common: Stevens-Johnson syndrome, drug induced toxic epidermolysis, Kawasaki disease +Less common: Scarlet fever, staphylococcal and streptococcal toxic shock syndrome +Vesicular rash +Common: Chickenpox, enteroviral infections (hand-foot-mouth disease) +Less common: Herpes simplex, herpes zoster, papulonecrotic tuberculosis +Petechial and/or Purpuric rash +Common: Meningococcemia, dengue hemorrhagic fever, Henoch-Schonlein purpura +Less common: Indian spotted fever, gonococcemia, hemorrhagic measles, chickenpox, cutaneous vasculitis +Urticaria! rash +Common: Scabies, insect bites +Less common: Cutaneous larva migrans due to hookworm, strongyloides, pediculosis +Nodular rash +Common: Erythema nodosum due to tuberculosis, drugs, sarcoid, inflammatory bowel disease, lepromatous leprosy; Molluscum contagiosum +Less common: Disseminated histoplasmosis, cryptococcosis +Infections and Infestations - + + + + + + + + + + + + + + + + + + +Fig. 10.3: Difuse eythematous rash seen in a patient with dengue + +Examination should include nature of the rash and its distribution, involvement of palms and soles (seen with dengue, spotted fever, Kawasaki disease and Stevens­ Johnson syndrome), involvement of mucous membranes, +lymphadenopathy, organomegaly and signs of meningeal irritation. Laboratory investigations that may assist +include complete blood counts, C-reactive protein, ESR, blood culture, specific serologies and sometimes, biopsy. + +Management +All efforts should be made to diagnose serious entities earlier and institute immediate treatment. For stable children, a specific diagnosis may not be always possible. In this situation, symptomatic therapy, close observation, explanation of danger signs to parents and staying away from school until the rash resolves, is recommended. +Often a child receives drugs and antibiotics for fever which is followed by a rash. Distinguishing this rash as a viral exanthem from drug related rash is difficult. Intense itching is more commonly seen with a drug rash. Withholding the drug, symptomatic therapy and observation is the usual practice. Rechallenge with the same drug later under observation is permitted if the rash was mild. + +Suggested Reading +Sarkar R, Mishra K, Garg VK. Fever with rash in a child in India. Indian J Dermatol Venereal Leprol 2012;78(3):251-62. + +COMMON VIRAL INFECTIONS Measles +Measles is a common and serious exanthematous illness, which still causes 350,000 childhood deaths annually in developing countries of which 80,000 occur in India alone. + +Etiopathogenesis +Measles is caused by an RNA virus belonging to the Paramyxovirus family. The virus is transmitted by droplet spread from the secretions of the nose and throat, usually + +4 days before to 5 days after the rash. The disease is highly contagious with secondary attack rates in susceptible household contacts exceeding 90%. The portal of entry is the respiratory tract where the virus multiplies in the respiratory epithelium. Primary viremia occurs resulting in infection of the reticuloendothelial system, followed by secondary viremia, which results in systemic symptoms. The incubation period is around 10 days. + +Clinical Features +The disease is most common in preschool children; infants are protected by transplacental antibodies, which generally decay by 9 months (hence the rationale for vaccination at this age). The prodromal phase is characterized by fever, rhinorrhea, conjunctiva! congestion and a dry hacking cough. Koplik spots, considered as pathognomonic of measles, appear opposite the lower second molars on the buccal mucosa on the second or third day of the illness as gray or white lesions resembling grains of sand with surrounding erythema. The rash, usually apparent on the fourth day with rise in fever, appears as faint reddish macules behind the ears, along the hairline and on the posterior aspects of the cheeks (Fig. 10.4). The rash rapidly becomes maculopapular and spreads to the face, the neck, chest, arms, trunk, thighs and legs in that order over the next 2-3 days. It then starts fading in the same order that it appeared and leaves behind branny desquamation and brownish discoloration, which fade over 10 days. +Modified measles, seen in partially immune individuals, is a milder and shorter illness. Hemorrhagic measles is characterized by a purpuric rash and bleeding from the nose, mouth or bowel. + +Complications +Widespread mucosal damage and significant immuno­ suppression induced by measles account for the frequent complications seen with this viral infection. Complications are more frequent in the very young, malnourished and the + + + + + + + + + + + + + + + +Fig. 10.4: Conjunctiva! congestion and morbilliform rash in a child with measles +----------------------------- +Essential Pediatrics + +immunocompromised. The most common complications are otitis media and bacterial bronchopneumonia. The usual bacterial pathogens are pneumococcus, Staphylococcus aureus and sometimes gram-negative bacteria. Other respiratory complications include laryngitis, tracheitis, bronchitis, giant cell pneumonia, bronchiectasis and flaring up of latent M. tuberculosis infection. Transient loss of tuberculin hypersensitivity reaction is common following measles. Gastrointestinal complications include persistent diarrhea, appendicitis, hepatitis and ileocolitis. Measles can precipitate malnutrition and can cause noma or gangrene of the cheeks. +Acute encephalitis occurs in measles at a frequency of +1 2- per 1000 cases, most commonly during the period of the rash, consequent to direct invasion of the brain. Post­ measles encephalitis occurs after recovery and is believed to be due to an immune mechanism, similar to other para­ infectious or demyelinating encephalomyelitis. Measles is also responsible for the almost uniformly fatal subacute sclerosing panencephalitis (SSPE), seen several yr after infection at a frequency of 1 per 100,000 cases. + +Diagnosis +The diagnosis is clinical and may be confirmed by estimating the levels of IgM antimeasles antibody that is present 3 days after the rash and persists for 1 month. Measles needs to be differentiated from other childhood exanthematous illnesses. The rash is milder and fever less prominent in rubella, enteroviral and adenoviral infections. In roseola infantum, the rash appears once fever disappears while in measles the fever increases with rash. In rickettsial infections, the face is spared which is always involved in measles. In meningococcemia, the upper respiratory symptoms are absent and the rash rapidly becomes petechial. Drug rashes have history of antecedent drug intake. In Kawasaki disease, glossitis, cervical adenopathy, fissuring of lips, extreme irritability, edema of hands and scaling are distinguishing clinical features. + +Treatment +Treatment is supportive and comprises antipyretics, maintenance of hygiene, ensuring adequate fluid and caloric intake and humidification. Vitamin A reduces morbidity and mortality of measles; a single oral dose of 100,000 units below 1 yr and 200,000 units over the age of 1 yr is recommended. Complications should be managed appropriately. + +Prevention +Measles is a preventable and potentially eradicable disease through universal immunization (see Chapter 9). + +Suggested Reading +Measles vaccines: WHO position paper. Wkly Epidemic! Rec 2009; 84:349-60 +Scott LA, Stone MS. Viral Exanthems. Dermatol Online J 2003;9:4 + +Varicella (Chickenpox) +Chickenpox is a mild exanthematous illness in most healthy children but can be a serious disease in neonates, immunocompromised, pregnant women and even healthy adults. + +Etiopathogenesis +Chickenpox is caused by the varicella zoster virus (VZV), a DNA virus of the herpes virus family. The virus is present in respiratory secretions and skin lesions of affected children and is transmitted by air-borne spread or direct contact. The portal of entry is the respiratory tract. During the incubation period of 10-21 days, the virus replicates in the respiratory mucosa followed by viremic dissemination to skin and various organs. The host immune responses limit infection and promote recovery. In immunocompromised children, unchecked replication and dissemination of virus leads to complications. During the latter part of the incubation period, the virus is transported to the respiratory mucosa and leads to infectivity even prior to appearance of the rash. The period of infectivity lasts from 24 to 48 hr before the rash until all the vesicles are crusted (the scabs are not infective, unlike small-pox). The disease is highly contagious with secondary attack rates of 80% among household contacts. VZV establishes lifelong latent infection in the sensory ganglia. Reactivation, especially during periods of depressed immunity, leads to the dermatomal rash of herpes zoster. + +Clinical Features +Chickenpox is rarely subclinical; however, in some children only a few lesions may be present. The peak age of disease is 5-10 yr. The prodromal period is short with mild to moderate fever, malaise, headache and anorexia. The rash appears 2-48 hr after the prodromal symptoms as intensely pruritic erythematous macules, seen first on the trunk. The rash rapidly spreads to the face and extremities while it evolves into papules, clear fluid-filled vesicles, clouded vesicles and then crusted vesicles (Fig. 10.5). Several crops of lesions appear and simultaneous presence of skin lesions in varying stages of evolution is characteristic of varicella. The median number of lesions is around 300 but may vary from 10 to 1500. Systemic symptoms persist for 2-4 days after appearance of the rash. The rash lasts 3-7 days and leaves behind hypopigmented or hyperpigmented macules that persist for days to weeks. Scarring is unusual unless lesions are secondarily infected. + +Complications +Secondary bacterial infections of the skin lesions is fairly common; necrotizing fasciitis is rare. Neurologic compli­ cations include meningoencephalitis, acute cerebellar ataxia, transverse myelitis, Landry-Guillain-Barre syndrome and optic neuritis. Other complications include purpura ful­ minans due to antibodies against protein C, CNS vasculitis +Infections and Infestations - + + + + + + + + + + + + + + + + + + +Fig. 10.5: Polymorphic rash of chickenpox + +leading to stroke, autoimmune thrombocytopenic purpura and Reye syndrome. +The progressive varicella syndrome is a dreaded complication in immunocompromised individuals, neo­ nates, pregnant women and even healthy adults and adolescents. This syndrome is characterized by continued development of lesions, hemorrhagic lesions, coagulopathy and visceral organ involvement including hepatitis, pneumonia and encephalitis. Mortality rate are high despite therapy. +Chickenpox in pregnancy is associated with an increased risk of severe disease in the mother. Congenital varicella syndrome may occur following infection in the first and second trimester at a frequency of 0.4-2%. It is characterized by skin scarring, malformed extremities, cataracts and brain abnormalities (e.g. aplasia, calci­ fications). Finally, if the disease occurs in the mother 5 days before to 2 days after delivery, severe and often fatal neonatal disease may result. +Herpes zoster in children is characterized by a mild vesicular rash with dermatomal distribution. Unlike in adults, pain is less and postherpetic neuralgia unusual. The risk of herpes zoster is more in immunocompromised children, children who acquire chickenpox in infancy and those whose mothers developed varicella in the third trimester. + +Diagnosis +The diagnosis is clinical and usually not difficult. Chickenpox should be differentiated from other vesicular exanthemata such as herpes simplex, enteroviral infections (hand-foot-mouth disease), insect bites and drug reactions. In atypical cases, the diagnosis is made on Tzanck smear of the lesions, which shows multinucleated cells and by demonstrating IgM antibodies to varicella. + +Treatment +Management is symptomatic and includes antipyretics, antipruritic agents and good hygiene. Aspirin is contra- + +indicated due to risk of Reye syndrome. The child should not attend school until new lesions stop appearing and all lesions have crusted. Administration of oral acyclovir (20 mg/kg/dose four times a day for 5 days) within 24 hr of onset of rash in healthy children reduces the duration of rash by one day and lesions by 25%. IV acyclovir (10 mg/ kg every 8 hr for 7 days) is given to patients with compli­ cated varicella and for illness in high risk patients (neo­ nates, immunocompromised children, pregnant women). + +Prevention +Prevention against varicella with the live attenuated varicella vaccine and use of varicella zoster immune globulin (YZIG) for postexposure prophylaxis are detailed in Chapter 9. YZIG is fairly expensive and not always available. + +Suggested Reading +Gershon AA: Varicella-zoster virus infections. Pediatr Rev 2008;29(1): 5-10 +Whitley RJ. Therapy of herpes virus infections in children. Adv Exp Med Biol 2008;609:216-32 + +Infectious Mononucleosis +Infectious mononucleosis, a syndrome characterized by fever, fatigue, sore throat and lymphadenopathy, is most often caused by a herpes virus, Epstein-Barr virus (EBY). Infectious mononucleosis-like illness can also be caused by toxoplasma, CMY, adenoviruses and primary HIV infection. + +Epidemiology +The EBY virus, a DNA virus of the herpes virus family, is transmitted in oral secretions by close intimate contact like kissing or exchange of saliva from close child contact. The virus replicates in the oral epithelial cells then spreads to salivary glands with eventual viremia to the B lympho­ cytes in the blood and lymphoreticular system including liver and spleen. The CDS lymphocytes proliferate to check this replication of virus in the B lymphocytes and represent the atypical lymphocytes seen in EBY infection. Like other herpes viruses, EBY establishes lifelong latent infection after the primary infection with frequent asymptomatic reactivations. +The epidemiology is related to the age of primary acquisition of EBY infection. In developing countries, most of EBY infection occurs in infancy and early childhood, when it is either asymptomatic or similar to other childhood infections. For this reason, infectious mononucleosis is uncommonly seen or reported in India. In developed countries, the age of acquisition of EBY infection shifts upwards and thus the illness is seen more commonly. + +Clinical Features +Symptomatic EBY infections in older children and adults are characterized by insidious onset of malaise, fatigue, +- Essential Pediatrics + + +fever, headache, nausea, sore throat, abdominal pain and myalgia. Examination shows pharyngeal inflammation with exudates and petechiae at the junction of soft and hard palate, generalized lymphadenopathy (cervical, less often axillary and inguinal), mild splenomegaly (50%) and hepatomegaly (10%). Maculopapular rashes are seen in 3-15% cases and in 80% of those who have received ampicillin or amoxicillin. +Complications are rare and include splenic rupture following minor trauma, airway obstruction due to enlargement of oropharyngeal lymphoid tissue, menin­ gitis, seizures, ataxia, myocarditis, hemolytic anemia, thrombocytopenia, neutropenia, aplastic anemia, inter­ stitial pneumonitis and pancreatitis. + +Diagnosis +Most patients show leukocytosis and absolute lympho­ cytosis, with presence of atypical lymphocytes on peripiheral smear. The platelet count is slightly low and hepatic transaminases mildly elevated in 50% patients. The Paul Bunnel (heterophile antibody) test is used for screening. This test is based on agglutination of sheep/ horse red cells by heterophile antibodies present in the serum of patients with EBV infection. This test may have false negative rates of 10% and remains positive for few months to 2 yr after infection. IgM antibody to viral capsid antigen (lgM VCA) is a confirmatory test to diagnose acute EBV infection. +Infectious mononucleosis should be differentiated from other causes of mononucleosis like illness, streptococcal pharyngitis and acute leukemia. + +Treatment +Rest and symptomatic therapy are advised. Participation in strenuous activities and contact sports should be prohibited in the first 2-3 weeks of illness due to risk of splenic rupture. Treatment with prednisolone (1 mg/kg/ day for 7 days) is advised for complications such as hemolytic anemia, airway obstruction, meningitis and thrombocytopenia with bleeding. + +Other Manifestations of EBV Infections +EBV has oncogenic potential and is causally associated with proliferative disorders such as virus associated hemophagocytic syndrome, oral hairy leukoplakia and lymphoid interstitial pneumonitis in patients with AIDS, nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin disease, tumors in immunocompromised patients (e.g. X­ linked lymphoproliferative disease, leiomyosarcoma, CNS lymphoma) and post-transplantation lymphoproliferative disease. + +Suggested Reading +Bell AT, Fortune B, Sheeler R. What is the best test for diagnosing infectious mononucleosis? J Fam Pract 2006;55(9):799-802 + +Roseola lnfantum +Roseola infantum or exanthem subitum or Sixth disease is a common childhood exanthematous illness caused by primary infection primarily by human herpes virus (HHV)-6 and less commonly by HHV-7 and echovirus 16. HHV-6 and HHV-7 are DNA viruses that target the CD4 T cells, and like other herpes viruses, can remain latent in the body for several yr after acute infection. +The peak age for roseola is between 6 months and 3 yr. The prodromal period is characterized by upper respira­ tory signs such as rhinorrhea, pharyngeal inflammation, conjunctiva! redness, mild cervical or occipital lympha­ denopathy and sometimes, palpebral edema. The classic clinical illness is heralded by high fever of 38-40°C, associated with febrile seizures in 5-10% cases, and lasts 3-4 days. Fever declines abruptly and is followed by development of a rash within 12-24 hr. The rash is discrete erythematous and maculopapular which first appears on the trunk and then spreads to the face, neck and proximal extremities. The rash is nonpruritic, rarely becomes confluent and fades in 3-4 days. Infectiousness is low and outbreaks have not occurred. Roseola should be differen­ tiated from childhood illnesses such as rubella, measles, enteroviruses and drug hypersensitivity. Treatment is symptomatic and prognosis excellent. + +Suggested Reading +Caserta MT, Mock DJ, Dewhurst S. Human herpes virus 6. Clin Infect Dis 2001;33:829-33 + +Erythema lnfectiosum +Erythema infectiosum or Fifth disease is a common exan­ thematous illness of childhood caused by a small DNA virus, parvovirus B19. This virus has tropism for cells of the erythroid lineage at the pronormoblast stage. +The peak age for erythema infectiosum is between 5 and 15 yr. Transmission of infection is by the respiratory route and the incubation period is 4-28 days (average 16-17 days). The prodromal phase is mild and consists of low-grade fever, headache and symptoms of mild upper respiratory tract infection. The characteristic rash first appears as erythematous flushing on the face in a 'slapped cheek' appearance (Fig. 10.6). It spreads rapidly to the trunk and proximal extremities as a diffuse erythematous macular rash that rapidly undergoes central clearing to give it a lacy or reticulated pattern. The rash gradually fades over a 1-3 week period. Complications include arthropathy, idiopathic thrombocytopenic purpura and aseptic meningitis. Fifth disease should be differentiated from measles, roseola, rubella and drug rash. Treatment is symptomatic. +Other serious manifestations of parvovirus B19 infection include arthralgia and arthropathy in adolescents or adults, transient aplastic crises in patients with chronic hemolytic anemias, chronic anemia, pancytopenia or marrow suppression, virus associated hemophagocytic +Infections and Infestations - + + + + + + + + + + + + + + + + + + + +Fig. 10.6: The rash resembles a 'slapped cheek' in erythema infectiosum +syndrome in the immunocompromised, hydrops fetalis in pregnant women and rare episodes of myocarditis in healthy children or adults. + +Suggested Reading +Servant-Delmas A, Lefrere JJ, Morine! F, Pille! S. Advances in human B19 erythrovirus biology. J Virol 2010;84:9658-65 +Servey JT, Reamy BV, Hodge J. Clinical presentations of parvovirus B19 infections. Am Fam Physician 2007;75:373-6 + +Mumps +Mumps is an acute viral infection characterized by painful enlargement of the salivary glands, most characteristically +the parotid glands. Mumps is caused by an RNA virus of genus Paramyxovirus in the family Paramyxoviridae; only one serotype is known. + +Epidemiology +Most cases occur between the ages of 5 and 15 yr; infants are rarely affected due to presence of transplacentally acquired maternal antibodies. Man is the only reservoir of infection; carrier state does not exist. The incidence is higher in winter and spring. +The virus is spread from human reservoir by direct contact, air-borne droplets and fomites contaminated by saliva and urine. The virus proliferates in the respiratory epithelium to enter the circulation and then gets localized to the glandular and neural tissue. The virus has been isolated from saliva as long as 6 days before to 9 days after appearance of salivary gland swelling. The secondary infection rate is as high as 80%. Mumps infection or immunization is believed to confer lifelong immunity. The disease is mild in the majority; in 10% cases, the infection is associated with aseptic meningitis or encephalitis. +Clinical Features +Following an incubation period of 2-4 weeks, symptoms +begin acutely with fever, malaise and headache. Mumps + +infection is characterized by unilateral or bilateral parotitis. This presents as earache, jaw tenderness while chewing, dryness of mouth and swelling at the angle of jaw. The ear lobe may appear to be pushed upwards and outwards. The defervescence and resolution takes about a week. Occasionally, other salivary glands, including the submaxillary and sublingual glands, are affected. +The occurrence of epididymoorchitis is more common in adolescent boys or postpubertal men. The condition is unilateral in 85% cases and occurs 1-2 weeks after parotitis. The testes are enlarged and tender. Some degree of atrophy follows the inflammation but sterility is rare. +Aseptic meningitis is seen in about 1-10% patients with parotitis. Mumps is perhaps the commonest cause of aseptic meningitis in children. Recovery is generally uneventful. The risk of encephalitis is between 0.02 and 0.3% cases. Mumps encephalitis has a satisfactory prog­ nosis with a mortality rate of less than 2%. Other neurological manifestations include auditory nerve damage leading to deafness, cerebellar ataxia, facial neuritis, transverse myelitis and Guillain-Barre syndrome. Uncommon presentations include pancreatitis (5% may trigger insulin dependent diabetes mellitus), mastitis, oophoritis, nephritis and myocarditis. + +Diagnosis +The diagnosis is based on clinical features and may be confirmed by ELISA for IgM. Serum amylase is elevated in almost 90% cases. Mumps parotitis needs to be differentiated from suppurative parotitis, submandibular lymphadenitis, recurrent juvenile parotitis, calculus in Stensen duct and other viral infections causing parotitis, e.g. coxsackie A and cytomegalovirus. + +Treatment +Symptomatic treatment is given in the form of antipyretics and warm saline mouthwashes. Orchitis is treated by bed rest and local support. Steroids may be used for sympto­ matic relief of orchitis and arthritis but does not alter the course of disease. + +Prevention +The affected patient should be isolated until the parotid swelling has subsided. Mumps can be prevented by timely immunization (Chapter 9). + +Suggested Reading +MacDonald N, Hatchette T, Elkout L, Sarwal S. Mumps is back: Why is eradication not working, Adv Exp Med biol 2011;697:197-220 +WHO position paper on mumps and vaccines. Weekly Epidemiologic Record 2001;76:345-56 + +Poliomyelitis +The polioviruses belong to the genus Enterovirus in the family Picornaviridae and comprise three related +- Essential Pediatrics + + + +serotypes: types 1, 2 and 3, all of which can cause paralysis. Type 1 is most frequently responsible, type 3 is less commonly causative and type 2 is only rarely implicated. + +Epidemiology +The disease is seasonal, occurring more commonly in summer and early autumn in temperate climates. In tropical countries, seasonality is less clearly defined; some areas experience increase in incidence during the rainy season. Feco-oral route is the predominant mode of transmission in developing countries with poor sanitation, whereas oral-pharyngeal transmission predominates in industrialized countries and during outbreaks. The average incubation period of disease is 7-10 days, ranging from 4 to 35 days. The virus is shed in the stools for 6-8 weeks after infection. +Humans are the only reservoir of poliovirus and infec­ tion is spread from person-to-person. The virus spreads rapidly to nonimmune persons. Transmission is usually widespread in the community by the time of onset of paralysis in a child. Infants born to mothers with antibodies are protected naturally against paralytic disease for a few weeks. Immunity is acquired through infection with the wild virus and through immunization. +The Global Polio Eradication initiative was launched in 1988 using oral polio vaccine (OPV) as the eradication tool and employing a four pronged strategy comprising (i) maintaining high routine immunization coverage, (ii) supplementary immunization activities (SIAs)/pulse immunization, (iii) acute flaccid paralysis (AFP) surveil­ lance, and (iv) outbreak response immunization. The initiative was hugely successful with reduction of polio cases from 350,000 worldwide in 1988 to 650 in 2011 and only 215 cases in 2012 (as of 25th December 2012). Only 3 countries, Afghanistan, Nigeria and Pakistan remain polio endemic; 210 of the 215 cases in 2012 were reported from these countries. The last wild polio case was reported from India on 13 January, 2011 and India is no more considered endemic for poliovirus. + +Pathogenesis +The mouth is the usual portal of entry. The virus is usually present in the pharynx and stools before the onset of paralytic illness. It invades local lymphoid tissue, enters the bloodstream to invade certain nerve cells and may damage or destroy these cells. + +Clinical Features +In 90-95% of individuals, poliovirus infection is inappa­ rent. In the remaining 5-10% of individuals, one of the following syndromes may occur. +Abortive polio occurs in 4-8% of infections and is characterized by a minor illness with low grade fever, sore throat, vomiting, abdominal pain, loss of appetite and malaise. Recovery is rapid and complete; there is no + + +paralysis. It cannot be distinguished from other viral infections. + +Nonparalytic aseptic meningitis occurs in 1-2% of infections, with headache, neck, back and leg stiffness several days after a prodrome similar to abortive polio. Recovery occurs within 2-10 days. + +Paralytic poliomyelitis occurs in 0.5-1 % of cases. Symptoms occur in two phases, minor and major, separated by several days without symptoms. The minor phase consists of symptoms similar to those of abortive poliomyelitis. The major phase of illness begins with muscle pain, spasms and the return of fever. This is followed by rapid onset of flaccid paralysis that is usually complete within 72 hr. + +Spinal paralytic poliomyelitis is the most common form of paralytic poliomyelitis, accounting for approximately 80% cases. It results from a lower motor neuron lesion of the anterior horn cells of the spinal cord and affects the mus­ cles of the legs, arms and/or trunk. Severe cases may deve­ lop quadriplegia and paralysis of the trunk, abdominal and thoracic muscles. The affected muscles are floppy and reflexes are diminished. The sense of pain and touch are normal. Paralysis is often asymmetrical, affecting legs more often than arms. Paralysis in extremities begins proximally and progresses to involve distal muscle groups (i.e. descending paralysis). Residual flaccid paralysis is usually present after 60 days. Bu/bar polio accounts for 2% cases and results from a cranial nerve lesion, resulting in respiratory insufficiency and difficulty in swallowing, eating or speaking. Bulbospinal polio accounts for 20% cases and is a combination of spinal paralytic and bulbar polio. + +Polio encephalitis is characterized by irritability, delirium and loss of consciousness; seizures may occur. The paralysis may be of the upper motor neuron type. +Depending on the strain of poliovirus, the ratio between subclinical and clinical cases is estimated to range between 100:1 and 1000:l. Older children and adults run a greater risk of developing paralytic illness. The case fatality rate among persons who develop the paralytic form of the disease is 2-20%. However, the case-fatality rate may be as high as 40% in those with bulbar or respiratory involvement. + +Residual Paralysis +Following an acute phase of illness lasting 1-4 weeks, the recovery of paralyzed muscles begins. The extent of recovery is variable ranging from mild to severe residual paresis at 60 days, depending upon the extent of damage caused to the neurons by the virus. Maximum neuro­ logical recovery takes place in the first 6 months of the illness; slow recovery continues up to two yr. After two year, no more recovery is expected and the child is said to have postpolio residual paralysis, which persists throughout life. +Infections and Infestations - + + +Diagnosis +The diagnosis is based on the history and the characteristic clinical manifestations of asymmetric flaccid paralysis. Stool examination is recommended in every case of acute flaccid paralysis (AFP). Virus can be detected from onset to 8 or more weeks after paralysis; the highest probability of detection is during the first 2 weeks after onset of paralysis. Examination of the cerebrospinal fluid (cell count, Gram stain, protein and glucose) is useful in eliminating other conditions that cause AFP. Current serologic tests cannot differentiate between wild and vaccine virus strains. Collection of blood specimens for culture or serology is not recommended. + +Differential Diagnosis +The two diseases most commonly confused with polio are Guillain-Barre syndrome and transverse myelitis. Other conditions with a presentation similar to those of paralytic poliomyelitis include traumatic neuritis and less fre­ quently, meningitis, encephalitis and illnesses produced by toxins (diphtheria, botulism) (see Chapter 19). + +Treatment +Treatment should be early and appropriate to the stage and +degree of paralysis. Children with bulbospinal polio and +respiratory paralysis require hospitalization. In the acute stage, children with isolated paralysis of one or more limbs can be managed at home. They should be advised complete rest, proper positioning of the affected limb and passive range of movement at the joints. Massage and intra­ muscular injection should be avoided during acute phase of illness. Frequent change of the posture of the patient is must. The child should be made to lie on a firm bed and maintain limbs in neutral position. The child should lie with trunk and hip straight with slight flexion (5-10°) at knees and feet at right angle at the ankle joint. This position can be maintained with pillows, rolled towels or sand bags. Warm moist fomentations can be given with soft towels, dipped in warm water to relieve pain and spasms. Analgesics can also be given to relieve pain and fever. All the joints of affected limb/limbs should be moved through their passive range of movements, 2-3 times a day for 10 times at each joint, to prevent joint stiffness. This helps to stimulate proprioceptive impulses from muscles and tendons, helping improve muscle power. +As the acute phase of illness subsides, recovery in muscle power is helped by giving physiotherapy, helping ambulation and prevention of deformities. Some children require orthosis at some stage for ambulation. Others with fixed deformities and contractures require orthopedic intervention. + +Prevention of Poliomyelitis +The available vaccines and the recommended schedule are discussed in Chapter 9. + +Eradication of Polio +Eradication is possible because polio affects only man, immunity is lifelong, a safe vaccine is available and there are no carriers or reservoirs of the infection. The strategies for achieving this goal are: +Attaining high rntes of routine immunization. Every child less than 1-yr-old should be immunized with at least three doses of oral poliovirus vaccine (OPV). +National immunization days (NIDs). On these days, under the pulse polio immunization (PPI) program, additional OPV doses are administered to every child <5-yr-old. The aim of NIDs/PPI is to 'flood' the community with OPV within a very short period, thereby interrupting trans­ mission of virus throughout the community. Intensi­ fication of the PPI program is accomplished by the addition of extraimmunization rounds, adding a house­ to-house 'search and vaccinate' component in addition to providing vaccine at a fixed post. The number of PPI rounds conducted during any particular yr is determined by the extent of poliovirus transmission in the state or district. +Mopping-up immunization. When poliovirus transmission is reduced to well-defined and focal geographic areas, intensive house-to-house, child-to-child immunization campaigns are conducted over a period of days to break the final chains of virus transmission. +Acute flaccid paralysis surveillance. Under the global polio eradication initiative, surveillance for polio is conducted through investigation of patients with AFP. AFP surveillance helps to detect reliable areas where poliovirus transmission is occurring. Acute flaccid paralysis (AFP) is defined as sudden onset of weakness and floppiness in any part of the body in a child <15-yr-old or paralysis in a person of any age in whom polio is suspected. In other parts of the world, at least one case of AFP (excluding polio) occurs annually for +every 100,000 children less than 15 yr of age (background +AFP rate). The nonpolio causes of AFP account for this background rate. Sensitive surveillance will detect a background AFP rate of 1 per 100,000 children. In our country, where the incidence of conditions such as traumatic neuritis and AFP caused by other nonpolio enteroviruses is +very high, the background nonpolio AFP rate is higher. +Details on the AFP surveillance are mentioned in Chapter 19. + +Suggested Reading +National Polio Survei.llance Project, at: http://www.npspindia.org/ index.asp. accessed on May 21,2012 +WHO position paper. Poliovaccines and immunization. Weekly epidemiologic record 2010;85:213-28 + +Hand-Foot-Mouth Disease +Hand-foot-mouth disease is a common viral illness primarily affecting children below 5 yr. It is caused by +- Essential Pediatrics + + +viruses of the genus Enterovirus belonging to family Picornaviridae, including polio, ECHO, coxsackie virus and enteroviruses. The most common causes of hand foot mouth disease are coxsackie virus A16 and enterovirus 71. The disease usually presents as outbreaks, often in preschool children and transmission is by direct contact with an affected patient or infected fomites. + +Clinical Features +The onset is with a prodrome characterized by low grade fever, feeling of being unwell and sore throat. This is followed by development of ulcers or blisters in the oral cavity, mostly on the posterior aspect and then a papulovesicular skin rash on the palms and soles and less commonly, on buttocks, knees, elbows and genital area (Fig. 10.7). All manifestations may not be present in all patients. The illness resolves quickly over 4-5 days. +Complications include temporary loss of toe nails or finger nails about 4 weeks after onset of disease. Rare complications include aseptic meningitis, encephalitis, polio like paralysis, myocarditis and respiratory distress syndrome. Outbreaks, particularly due to enterovirus 71, are reported from China, Vietnam, Taiwan and Malaysia, in which neurologic complications are common and mortality significant. Some experts believe that entero­ viruses cause hand-foot-mouth disease now occupy the ecologic niche vacated by eradication of polioviruses. +Diagnosis is clinical and requires differentiation from other illnesses causing oral ulcers like herpangina, herpetic gingivostomatitis and aphthous ulcers and from chicken­ pox. + +Treatment and Prevention +Treatment is mainly symptomatic and includes analgesics and soft diet. Isolation of affected children at home and promotion of hand hygiene to prevent disease spread is important. No vaccine is available against this disease. + +Suggested Reading +Wong 55, Yip CC, Lau SK, Yuen KY. Human enterovirus 71 and hand, foot and mouth disease. Epidem.iol nfect 2010;138:1071--89 + + + + + + + + + + + + + + +Fig. 10.7: The vesicular rash of hand-foot-mouth disease + +VIRAL HEPATITIS +Hepatitis, meaning inflammation of the liver, can be caused by a variety of different hepatotropic viruses such as hepatitis A, B, C, D and E. Hepatitis A and E are responsible for most of the water-borne (community acquired) hepatitis while B, C and D are responsible for post-transfusion hepatitis. Since a considerable number of cases of post-transfusion and community-acquired hepatitis are not identified as being caused by hepatitis A-E, other hepatotropic viruses are also incriminated, including hepatitis G, TI virus and SEN virus. + +Hepatitis A +Hepatitis A is caused by infection with the hepatitis A virus (HAV), a nonenveloped RNA virus. A single serotype of HAV infects humans and infection induces lifelong immunity. HAV is extremely resistant to degra­ dation by environmental conditions. Hence, it spreads readily by the feco-oral route through contaminated food and water and from person-to-person living with poor sanitation. Disease severity increases with age at infection; children below 5 yr age have asymptomatic infection or present with an acute undifferentiated febrile illness, while older children, adolescents and adults suffer from classic hepatitis. Symptomatic disease is uncommon and outbreaks rare in developing countries with poor hygiene since most individuals are infected in childhood. In regions with intermediate endemicity like India, a significant proportion of people escapes infection in childhood and may develop symptomatic disease as adults. + +Clinical Features +During an incubation or preclinical period of average 30 (range 10-50) days, the virus replicates actively. This is followed by a short prodromal phase lasting up to a week, which is characterized by loss of appetite, fatigue, abdominal pain, nausea and vomiting, fever, diarrhea, dark urine and pale stools. Older individuals then have an icteric phase, during which jaundice develops, with total bilirubin levels exceeding 2-4 mg/ dl. Fever improves after the first few days of jaundice. In the subsequent few weeks of convalescence, patients show complete recovery. +In around 0.1-1% of patients, extensive necrosis of the liver occurs during the first 6-8 weeks of illness. In this case, high fever, marked abdominal pain, vomiting, jaundice and the development of hepatic encephalopathy associated with coma and seizures occur. These are the signs of inant hepatitis which is more common as age advances and leads to death in 70-90% of the patients. In patients who survive, neither functional nor pathologic sequelae are common despite the widespread necrosis. Infection with HAV does not lead to chronic or persistent hepatitis. Relapsing hepatitis may occur in 3-20% of patients 4 to 15 weeks after the initial symptoms have resolved. +Infections and Infestations - + + + +Diagnosis +The specific diagnosis of acute hepatitis A is made by detecting serum anti-HA V IgM. Anti-HA V IgM is detectable about 3 weeks after exposure, by which time symptoms have already appeared. Its titer increases over 4-6 weeks, then declines to nondetectable levels within 6 months of infection. As IgG anti-HAV persists lifelong after acute infection, detection of IgG anti-HAV alone indicates past infection. Laboratory evaluation of liver function includes estimation of total and direct bilirubin, transaminases, alkaline phosphatase, prothrombin time, total protein and albumin. + +Treatment +Therapy is supportive and is aimed at maintaining adequate nutrition. There is no evidence to suggest that restriction of fats has any beneficial effect on the course of the disease. Eggs, milk and butter may actually help provide an appropriate caloric intake. Antiviral agents have no role because the hepatic injury appears to be immunologically mediated. Referral to a liver transplant center is appropriate for patients with fulminant hepatitis. + +Prevention +The ideal preventive strategy is improvement in sanitation, hygiene and water supply. Immunization is very effective and discussed further in Chapter 9. Immunoglobulin G may be used for postexposure prophylaxis. If adminis­ tered within two weeks of exposure it either prevents development of disease or reduces its severity. + +Suggested Reading +Mathur P, Arora NK. Epidemiological transition of hepatitis A in India: issues for vaccination in developing countries. Indian J Med Res 2008;128:699-704 + +Pathogenesis and Natural Course +HBV has an incubation period of 2--6 months. Following primary HBV infection, an acute, fulminant or chronic course may be noted. + +Acute and fulminant hepatitis. Acute hepatitis is marked by symptoms similar to other acute hepatitis illnesses, i.e. fever, vomiting, jaundice and anorexia. Recovery is marked by hepatitis B surface antibody (anti-HBs) seroconversion. Fulminant hepatitis is heralded by pathologic mental status changes within 2 to 8 weeks after the initial symptoms in an otherwise healthy child. About two-thirds of children with fulminant hepatitis B present in infancy. + +Chronic infection. Children with chronic HBV infection are mostly asymptomatic. They are generally active and grow well. Although liver damage is usually mild during childhood, serious sequelae, including cirrhosis and hepatocellular carcinoma, may develop insidiously at any age. An immune-mediated process is the main mechanism for cell damage. During acute exacerbations of chronic HBV infections, CD8+ T lymphocytes are the predominant cells in the liver in the areas of piecemeal necrosis. Since HBeAg is an important marker reflecting active viral replication and infectivity, its clearance is used as a marker for the success of antiviral therapy. Children with chronic HBV infection are HBeAg seropositive at the initial stage of infection; this antigenemia can persist for yr after primary infection (Fig. 10.8). Spontaneous clearance of HBeAg occurs gradually with increasing age. Viral replication is reduced during this process. This process of HBeAg seroconversion takes place subclinically in most individuals for a period of 2 to 7 yr (Table 10.3). This process is usually preceded by an elevation of amino­ transferases. After HBeAg clearance, aminotransferase + + + +Hepatitis B +Hepatitis B virus is a 3.2 kb, circular, partially double stranded DNA virus. HBV contains four open reading frames, which encode major structural and nonstructural proteins for HBV. + +Epidemiology + + +Acute +(6 months) + + +Chronic (years) +HBeAg l·MUl#i=tl +HBsAg + +Total anti-HBc + + + +HBV infection is prevalent in Asia, Africa, Southern Europe and Latin America, where the HBsAg sero­ positivity ranges from 2 to 20%. In hyperendemic areas, HBV infections occur mainly during infancy and early childhood. In Asia, perinatal transmission from HBsAg carrier mothers to their infants is an important route of transmission leading to chronicity. Approximately 90% of infants of HBeAg seropositive carrier mothers become HBsAg carriers, irrespective of a high or low HBsAg carrier rate in the population. In areas of low endemicity, horizontal infection is the main route of transmission. + + + + +lgM anti-HBc + + + +/1 I +O 4 8 12 16 20 24 28 32 36 II 52 /I Years Weeks after exposure + +Fig. 10.8: Serological response in hepatitis B virus infection +- Essential Pediatrics + + +Table 10.3: Common seropatterns of hepatitis B infection + +HBsAg Anti-HBs + + ++ + + + ++ + + + +Anti-HBc HBeAg IgM + ++/­ +IgM +IgG + IgG ++/­ IgG IgG + +Anti-HBe + ++/- + ++ + ++/­ ++/- + +Interpretation +Acute infection +Acute infection; anti-HBc window Chronic infection; high infectivity Chronic infection; low infectivity Precore/Core mutant infection Hepatitis B carrier +Recovery from infection +Immunization; false positive; infection in remote past + + + +levels return to normal levels and anti-HBe develops. Longterm followup of HBsAg carrier children shows that the rate of HBsAg clearance is low (0.6% annually), and occurs only after clearance of HBeAg. +During the early phase of infection, the amount of virus in the liver and blood is usually large, whereas the liver damage is mostly mild. The host immune system gradually recognizes the virus and starts to clear the virus. It results in active inflammation of the liver and elevation of serum aminotransferases. Repeated episodes of elevation of aminotransferases is followed by HBeAg seroconversion. After HBeAg seroconversion, viral replication declines and the liver inflammation gradually becomes inactive. + +Treatment +There are two approved therapies for chronic hepatitis Bin children: interferon (IFN) and lamivudine. Interferons are a group of naturally occurring agents with antiviral, antineoplastic and immunomodulatory properties. IFNa2a achieves seroconversion in approximately one­ third of cases; those most likely to respond have high ALT activity and a greater histological activity index score in the liver biopsy before treatment. Children younger than 6 yr have an enhanced response to IFNa2b treatment. Side effects of IFN in children are flu-like symptoms, headache, depression, loss of appetite, anemia, leukopenia and thrombocytopenia. Promising results are emerging using pegylated IFN in adults with chronic hepatitis B, but data in children are lacking. +Lamivudine monotherapy for 1 yr provides satisfactory results in children with chronic hepatitis B. Children with higher pretreatment ALT levels and histologic activity index scores are most likely to respond to lamivudine. The medication is well tolerated, has minimal side effects and is easy to administer. However, the development of resistant viral mutants (YMDD) limits the benefit of longterm monotherapy. Combinations of either INFa2a or INFa2b with lamivudine have comparable effects and slightly better results than monotherapy in children affected by chronic hepatitis. Other drugs including adefovir, entecavir and dipivoxil have documented clinical activity against wild and lamivudine resistant HBV, but needs to be further evaluated in children. + +lmmunoprophylaxis +Hepatitis B irnunoglobulin is used in the postexposure prophylaxis of newborns of HBV infected women. It is administered intramuscularly and may be given con­ currently with HBV vaccine, at a different site. The dose for infants is 0.5 ml. Combination of the irnunoglobulin and HBV vaccination in infants born to HBsAg positive mothers prevents transmission in approximately 95% of those at risk. + +Hepatitis D +Hepatitis delta virus (HOV) was first detected as a new nuclear antigen in the hepatocytes of patients infected with hepatitis B virus (HBV) and was frequently associated with severe acute or chronic hepatitis. Transmission of hepatitis delta virus requires either coinfection with HBV or superinfection in individuals who are HBV carriers. + +Hepatitis C +Hepatitis C virus (HCV) was recognized in 1989 as a major cause of non-A, non-B hepatitis. HCV is an enveloped, single-stranded, positive-sense ribonucleic acid virus, classified as an independent genus (Hepacivirus) within the Flavivirus family. + +Viral Variants +The HCV RNA-dependent RNA polymerase lacks proof­ reading ability, which results in HCV being genetically heterogeneous. Based on analysis of HCV sequences, six major HCV genotypes are recognized. HCV genotypes 1 and 2 are the most prevalent worldwide. HCV genotype 3 is most common in Australia and the Indian sub­ continent. The viral genotypic distribution in children generally parallels that reported regionally in adults. HCV genotype 1 correlates with higher serum viral levels and a less favorable response to antiviral treatment. + +Epidemiology +The worldwide prevalence of HCV infection is approxi­ mately 3%, which represents an estimated 170 million infected persons. Children who received transfusions of potentially contaminated blood products prior to the institution of routine screening have seroprevalence rates up to 95%. +Infections and Infestations - + + + +Clinical Features +The mean incubation period of post-transfusion acute HCY infection is 7 to 8 weeks, with a range of 2 to 26 weeks. Acute HCY is usually anicteric or subclinical and only one-third of patients develop jaundice or symptoms. Fulminant hepatic failure due to HCY is rare. In adults, 85% of patients exposed to HCY will develop chronic infection, of which approximately 10 to 20% develop cirrhosis. In children, the course of HCY infection is generally benign. Most children with acute hepatitis C are asymptomatic. +When symptoms are present, they are often nonspecific (malaise, anorexia) or mild; jaundice is present in 25%. Most children exposed to HCY are at risk to become chronically infected based on persistently detectable serum anti-HCY antibodies and HCY RNA Children with chronic HCY infection may also remain asymptomatic. Progression to decompensated liver disease in children is rare. Biochemical markers such as serum alanine aminotransferase typically fluctuate in HCY patients. Normal or only minimally increased transaminase levels are reported with chronic HCY infection and these can remain elevated despite anti-HCY seronegativity. Liver histology shows portal lymphoid aggregates, bile duct injury and steatosis; necroinflammatory activity is mild. + +Perinatal Transmission +The rate of vertical transmission is approximately 5-6%, which is low compared to that for hepatitis B virus and human immunodeficiency virus. High-titer maternal viremia correlates with higher transmission rates. Breastfeeding is permitted unless the mother has bleeding nipples. + +Diagnosis +The diagnosis of HCY infection is based on detection of antibodies against recombinant HCY antigens by enzyme immunoassay or recombinant immunoblot assay or by detection of HCY RNA using nucleic acid tests. Enzyme immunoassay is limited by frequent false-positive results, particularly in patients with elevated globulin levels such as those with autoimmune hepatitis. Recombinant immunoblot assays are less sensitive but more specific than enzyme immunoassay in detecting anti-HCY antibodies. Recombinant immunoblot assay is, therefore, not recommended for initial HCY screening and are useful to confirm viral infection. Nucleic acid tests identify the presence of HCY very early in the course of infection and therefore, are used to diagnose infection even before the anti-HCY antibodies have appeared. These tests are also necessary to detect HCY in infants born to infected mothers, in whom HCY antibodies may be of maternal origin and in immuno­ compromised patients whose ability to produce HCY antibodies may be impaired. + +Therapy +Sustained virologic responses are achieved in only 8-35% of patients given recombinant interferon monotherapy. However, significantly higher sustained virologic respon­ ses are attained (30-40%) by combining interferon with riba virin at 15 mg/kg/day. Longer-acting pegy lated inter­ ferons have been subsequently developed based on the premise that more sustained drug levels would result in greater antiviral activity. Several randomized clinical trials in adults verify considerably better virologic responses (50-60%) with the use of pegylated interferons, particu­ larly when given in conjunction with ribavirin. However, in general, sustained virologic response rates in children treated with interferon alone (30-60%) appear to be two­ to three-fold higher than in similarly treated adults. Importantly, biochemical and virologic responses have been accompanied by significant histologic improvement in all treated patients included in these trials, and interferon has been well tolerated in children. + +Suggested Reading +Heller S, Valencia-Mayoral P. Treatment of viral hepatitis in children. Arch Med Res 2007;38:702-10 +Hsu EK, Murray KF. Hepatitis B and C in children. Nat Clin Pract Gastroenterol Hepatol 2008;5:311-20 +Price N, Boxall EH. Treatment of children persistently infected with +hepatitis B virus: seroconversion or suppression. J Antimicrob Chemother 2007;60:1189-92 + +Hepatitis E +Hepatitis E virus was first described in 1978 after an epidemic affecting 52,000 individuals in Kashmir. Hepatitis E is caused by infection with the hepatitis E virus (HEY), a single-stranded RNA virus. Just like hepatitis A virus, HEY is transmitted via the fecal oral route. It is usually transmitted through contaminated drinking water. Hepatitis E virus causes acute sporadic and epidemic viral hepatitis. Symptomatic HEY infection is most common in young adults aged 15-40 yr and is uncommon in children since it is mostly asymptomatic and anicteric. + +Clinical Features +The incubation period following exposure to HEY ranges from 3 to 8 weeks, with a mean of 40 days. The clinical presentation of hepatitis E is similar to hepatitis A The severity of an HEY infection is generally greater than the severity of an HAY infection. In pregnant women, the disease is particularly severe where mortality approaches 20% with infections in the third trimester. Premature deliveries with high infant mortality up to 33% are observed. No evidence of chronic inflammation or of a healthy chronic carrier state has been detected and no recurrence of hepatitis E has been reported. + +Diagnosis +Laboratory evaluation of HEY is similar to that of HAY and is based on detection of IgM antibodies. These +- Essential Pediatrics + + + +antibodies (IgM and IgG) develop at the time symptoms occur, usually before the development of jaundice. IgM anti-HEY titer declines rapidly during early convale­ scence, while IgG anti-HEY persists for long duration and provides protection against subsequent infections. + +Treatment +As no specific therapy is capable of altering the course of acute hepatitis E infection, prevention is the most effective approach against the disease. + +Prevention +Good personal hygiene, high quality standards for public water supplies and proper disposal of waste have resulted in a low prevalence of HEV infections in developed countries. At present, there are no commercially available vaccines for the prevention of hepatitis E. + +Hepatitis due to other Viruses +Certain cases of post-transfusion (10%) and community acquired hepatitis (20%) are of unknown origin. Three viruses are potentially associated with liver disease but no conclusive evidence exists to support them as a cause for these cases. These viruses are HGV /GB virus C, TT virus and SEN virus. + +Suggested Reading +Aggarwal R, Jameel S. Hepatitis E. Hepatology 2011 Dec;54:2218-26 + +Dengue Infections +Dengue fever is an acute illness characterized by fever, myalgia, arthralgia and rash. Severe dengue infection is characterized by abnormalities in hemostasis and by marked leakage of plasma from the capillaries; the latter may lead to shock (dengue shock syndrome). + +Epidemiology +The global prevalence of dengue has grown dramatically in recent decades. The disease is now endemic in more than 100 countries in Africa, the Americas, the Eastern Mediterranean, South-East Asia and the Western Pacific. WHO currently estimates there may be 50 million cases of dengue infection worldwide every year. During epidemics of dengue, attack rates among susceptible are often 40-50%, but may reach 80-90%. An estimated 500,000 cases of severe dengue infection require hospitalization each year, of which very large proportions are children. Without proper treatment in severe dengue infection [earlier called dengue hemorrhagic fever (DHF) dengue shock syndrome (DSS)] case fatality rates can exceed 20%. +The spread of dengue is attributed to expanding geographic distribution of the four dengue viruses and of their mosquito vectors, the most important of which is the predominantly urban species Aedes aegypti. A rapid rise in urban populations is bringing ever greater numbers + + +of people into contact with this vector, especially in areas that are favorable for mosquito breeding, e.g. where household water storage is common and where solid waste disposal services are inadequate. + +Virus. Dengue fever is caused by infection due to any of the four serotypes of dengue viruses. Dengue viruses are arboviruses that belong to the family Flaviviridae. The envelop protein bears epitopes that are unique to the serotypes; the antibodies to these unique epitopes neutralize by interfering with the entry of the virus into the cells. +Transmission. Dengue viruses are transmitted to humans through the bites of infected female Aedes mosquitoes. Mosquitoes generally acquire the virus while feeding on the blood of an infected person. After incubation for 8-10 days, an infected mosquito is capable, during probing and blood feeding, of transmitting the virus, to susceptible individuals for the rest of its life. Infected female mosquitoes may also transmit the virus to their offspring by transovarial transmission, but the role of this in sustaining transmission of virus to humans has not yet been delineated. Humans are the main amplifying host of the virus, although studies have shown that in some parts of the world monkeys may become infected and perhaps serve as a source of virus for mosquitoes. The virus circulates in the blood of infected humans for two to seven days, at approximately the same time as they have fever; Aedes mosquitoes may acquire the virus when they feed on an individual during this period. + +Pathophysiology +The major pathophysiologic changes that determine the severity of disease in severe dengue infection and differentiate it from dengue fever are plasma leakage and abnormal hemostasis leading to rising hematocrit values, moderate to marked thrombocytopenia and varying degrees of bleeding manifestations. The cause of abnormal leakage of plasma is not entirely understood. However, rapid recovery without residual abnormality in vessels suggests it to be the result of release and interaction of biological mediators, which are capable of producing severe illness with minimal structural injury. +It has been observed that sequential infection with any two of the four serotypes of dengue virus results in severe dengue infections in an endemic area. How a second dengue infection causes severe disease and why only some patients get severe disease remains unclear. It is suggested that the residual antibodies produced during the first infection are able to neutralize a second viral infection with the same serotype. However, when no neutralizing antibodies are present (i.e. infection due to another serotype of dengue virus), the second infection is under the influence of enhancing antibodies and the resulting infection and disease are severe. An alternative expla­ nation is that certain strains (South-East Asian) of the dengue virus may be inherently capable of supporting +Infections and Infestations - + + + +severe antibody-enhanced infection than viruses in other geographic area. Serotype cross-reactive antibodies generated from previous primary infection with a particular dengue viral serotype are not highly specific for the other serotypes involved in secondary infections. Hence, they bind to the virions but do not neutralize them, and instead increase their uptake by cells, which express Fe. receptors on their surfaces, like tissue dendritic cells, monocytes and macrophages. Such antibody-coated virions are taken up more rapidly than uncoated virus particles and this leads to enhanced antigen presentation by the infected dendritic cells to the T cells, leading to the more rapid activation and proliferation of memory T cells. The cytokines produced by the activated T cells have several important effects that lead to the pathogenesis of the severe dengue infections (DHF /DSS). Cytokines are also implicated in the pathogenesis of vascular compromise and hemorrhage in dengue virus infection. Endothelial cell dysfunction in dengue virus infection manifests as diffuse increase in capillary permeability, which is responsible for the microvascular leakage, hemo­ concentration and circulatory insufficiency. The transient nature of plasma leakage suggests that it could be +mediated by a soluble mediator. +Dengue viral infection is commonly associated with thrombocytopenia, the cause of which is molecular mimicry between dengue virus proteins and endogenous self proteins. There is generation of antibodies against dengue virus proteins (especially NSl), which cross-react with platelet surface proteins and thus cause thrombo­ cytopenia. There is activation of blood clotting and fibrinolytic pathways. Mild disseminated intravascular coagulation, liver injury and thrombocytopenia together contribute to hemorrhagic tendency. Central nervous system involvement also has been identified and has been attributed to direct neurotropic effect of dengue virus. + +Pathology +There are usually no gross or microscopic lesions that may account for death, except when massive gastrointestinal or intracranial bleeding causes death. Presence of viruses in tissues mainly leads to hemodynamic alterations with generalized vascular congestion and increased permeability, and mast cell recruitment in lungs. These findings have also been seen in animal models. Variable hepatic involvement has been reported-diffuse hepatitis withmidzonal necrosis and steatosis, focal areas of necrosis and normal histology in some children. Dengue virus antigen can be detected using rnunohistochemistry in hepatocytes from necrotic areas. Absence of recruitment of polymorphonuclear cells and lymphocytes has been observed in the liver lesions of patients who died from DHF. + +Clinical Manifestations +Dengue infection has varying clinical presentations and often with unpredictable clinical evolution and outcome. + + +Incubation period is 4-10 days. Most infections are subclinical. Infants and young children may present with an undifferentiated febrile illness. The classic presentation of dengue fever is usually seen in older children, adoles­ cents and adults and can be described under three phases. + +Febrile phase. It is characterized by sudden onset high­ grade fever that may last for 2-7 days. There may be facial flushing, skin erythema, generalized bodyache, myalgia, arthralgia, headache, anorexia, nausea and vomiting. Occasionally, child may have sore throat, injected pharynx and conjunctiva! injection. A positive tourniquet test may be seen in some patients. Minor hemorrhagic mani­ festations: petechiae and mucosal bleeding (e.g. nose and gums) may be seen in some patients. Liver may be enlarged and tender from 2-5 days and indicates risk for development of severe illness. There is progressive decrease in total white cell count and platelet count. + +Critical phase. This phase is between 3 and 7 days of onset of fever when defervescence sets in. Child may develop bleeding and shock with fall in platelet count and increase in packed cell volume. Some children may develop organ dysfunction such as severe hepatitis, encephalitis or myocarditis and/or severe bleeding (may also develop without obvious plasma leakage or shock). + +Recovery phase. After 24-48 hr in critical phase, a gradual reabsorption of extravascular compartment fluid takes place in 48-72 hr. General wellbeing improves, appetite returns, gastrointestinal symptoms abate, hemodynamic status stabilizes and diuresis ensues. Some patients may have a rash of "isles of white in the sea of red". Some may experience generalized pruritus, bradycardia and electrocardiographic changes; respiratory distress may occur due to pulmonary edema. The packed cell volume stabilizes or may be lower due to the dilution; leukocyte count starts to rise soon after defervescence, while recovery of platelet count takes longer. + +Differential Diagnosis +Differential diagnosis for dengue infection includes other hemorrhagic fevers, influenza, malaria, enteric fever, leptospirosis, less commonly meningococcemia and rickettsial infections. Malaria, leptospirosis, flu and enteric fever may also be coinfected with dengue. Wide spread chikungunya virus infections have occurred in various parts of India and South-East Asia. Its clinical mani­ festations are similar to dengue. However, fever is of shorter duration, thrombocytopenia and bleeding are less. Other clinical features that are more common in chikun­ gunya are skin eruptions, mucosal lesions, polyarthralgia and encephalopathy. Since dengue as well as chikungunya infections are endemic in most parts of India, both infections may occur together. +__ E_s_s_e_n_t.ia_r_P_e _d.ia..t r_ic_s __________________________________ +_ + + +The following clinical and laboratory features suggest presence of severe dengue infection: +Clinical criteria. Acute onset high-grade fever, hemorrhagic manifestations (at least a positive tourniquet test), tender hepatomegaly, effusion in body cavities and or shock. +Laboratory criteria. Thrombocytopenia (1,00,000 cells per cubic mm or less or less than 1-2 platelets per oil immersion field), rising hematocrit. + +Laboratory Investigations +During the course of illness, children with severe dengue infection show increasing packed cell volume, low platelet count and decreasing leukocyte count with increasing lymphocytes. A low leukocyte count in a child with febrile illness during the endemic season suggests possible dengue infection. However, malaria and typhoid/ paratyphoid may also present with low leukocyte count. Serum chemistry may show decrease in total protein and albumin, which is more marked in patients with shock. Levels of transaminases are raised. A higher increase in SGOT than SGPT suggests a possibility of dengue infection rather than other viral infections. In severe cases there may be hyponatremia, and acidosis +along with increase in urea and creatinine. +X-ray film of the chest or ultrasound examination may show varying degrees of pleural effusion, commonly on the right side, occasionally bilateral. Ultrasonography of abdomen may show ascites and enlarged gallbladder due to wall edema. +Confirmation of diagnosis of dengue may be established by following: +i. Direct methods, including (a) virus isolation by culture; (b) genome detection by PCR; (c) NSl antigen detection +ii. Indirect methods, including (a) IgM detection; and (b) IgG detection + +Virus isolation or PCR requires the sample to be obtained within the first 5 days of fever, is technically demanding, not universally available, expensive and hence of limited practical use. NSl antigen is a highly conserved glycoprotein of dengue virus and secreted during the initial phase of illness. It disappears as the antibodies appear and hence declines as illness advances and in secondary dengue infections. The specificity is near 100% and sensitivity in the first four days of illness is 90% in primary dengue and 70% in secondary dengue infection. +Antibody determination needs careful interpretation. Following primary dengue infection, 80% of patients will have detectable IgM antibodies by day 5 and 99% by day 10. IgM antibodies peak by day 14 and are undetectable by two to three months. IgG antibodies rise later, peak to levels lower than IgM, decline slowly and remain detectable at low levels for life. Therefore, diagnosis of primary dengue infection is based on elevation of IgM. + +Management +Patients with dengue infection can be classified as asymptomatic, or symptomatic as follows: +i. Undifferentiated fever +ii. Dengue without warning signs iii. Dengue with warning signs +iv. Severe dengue infection. +Undifferentiated fever. Patients may have nonspecific symptoms. Treatments consist of paracetamol for fever and regular monitoring for development of any compli­ cations. + +Dengue infection without warning signs. Patients with fever, bodyaches, rashes or minor bleeding may be treated symptomatically. Fever and bodyaches are best treated with paracetamol. Salicylates and other nonsteroidal anti­ inflammatory drugs should be avoided as these may predispose to mucosal bleeds. Child should be encouraged to drink plenty of fluids. There is no specific therapy. In epidemic situations the primary care physician/health care worker should monitor the patient for waing signs (given below) along with hematocrit and platelet counts if possible. + +Dengue with warning signs. Children with suspected dengue infection who have any of the following needs hospitalization: (i) abdominal pain or tenderness; (ii) persistent vomiting; (iii) clinical fluid accumulation; (iv) mucosal bleed; (v) lethargy, restlessness; (vi) liver enlargment >2 cm; and (vii) laboratory features like increase in packed cell volume (hematocrit) with concurrent with rapid decrease in platelet count. +These patients require admission to the hospital and need intravenous fluids, preferably crystalloids. All children without hypotension should be given Ringer lactate or normal saline infusion at a rate of 7 ml/kg over one hour. After one hour if the hematocrit has decreased and vital parameters are improving; fluid infusion rate should be decreased to 5 ml/kg over next hour and to 3 ml/kg/hr for 24-48 hr with frequent monitoring of hematocrit and vital parameters. When the patient is stable as indicated by normal blood pressure, good oral intake and urine output, the child can be discharged (Fig. 10.9). If at one hour, the hematocrit is rising and vital parameters do not show improvement, fluid infusion rate is increased to 10 ml/kg over next hour. In case of no further improvement, fluid infusion rate is further increased to 15 ml/kg over next hour (third hr). If no improvement is observed in vital parameters and hematocrit at the end of 3 hr; colloids or plasma infusion in doses of 10 ml/kg is administered. Once the hematocrit and vital parameters are stable the infusion rate is +gradually reduced and discontinued over 24-48 hr. +Severe dengue. Children presenting/ developing any of the following are included: +Infections and Infestations - +• +• +• + + + +Dengue fever with risk factors + +[ Hospitalize + +Ringer lactate (RL) 7 ml/kg/hr + +Assessment at one hr; vitals and hematocrit + + +No improvement Improvement +i +• ++ +RL 10 ml/kg/hr RL 5 ml/kg/hr + +Assessment at 2 hr Further improvement + +No improvement RL 3 ml/kg/hr j ++ +f +J +--l===---- +i=- + +RL 15 ml/kg/hr ntinue IV fluids unlil1 +stable for 24 hr + +Assessment at 3 hr Discharge when stable for 24-48 hr +�- + +No improvement +- +f- +.. +1 Colloids 10 ml/k�--� +- +- +r No improve� + +I Look for anemia, acidosis and myocardial dysfunction: treat accordingly + +Fig. 10.9: Management algorithm for dengue fever with risk factors + +• Severe plasma leakage leading to: - Shock +- Fluid accumulation with respiratory distress +• Severe bleeding as evaluated by clinician +• Severe organ involvement +- Liver: AST or ALT '.1000 IU/1 - CNS: Impaired consciousness - Heart and other organs +Children classified as severe dengue should be hospitalized (preferably in Pediatric Intensive Care Unit) and treated with normal saline or lactated Ringer solution; 10-20 ml/kg is infused over one hr or given as a bolus if blood pressure is unrecordable (earlier known as dengue shock syndrome DSS IV). In critically sick children it is preferable to establish two IV lines, one for administration of normal saline and other for infusing 5% dextrose and potassium. If there is no improvement in vital parameters and the hematocrit is rising; colloid 10 ml/kg is infused rapidly. Alternatively, if hematocrit is falling without any improvement in vital parameters; blood transfusion should be given with the presumption that lack of improvement is due to occult blood loss (Fig. 10.10). Once improvement starts then fluid infusion rate is gradually + +decreased. In addition to fluid management, oxygen should be administered to all patients with shock. +Management of bleeding +a. Petechial spots or mild mucosa/ bleed but hemodynamically stable. Such patients needs supportive care including bed rest, maintenance of hydration and monitoring. Avoid IM injections. There is no role of prophylactic platelet rich plasma (PRP) infusions even with severe thrombocytopenia. Avoid any procedures predispos­ ing to mucosal trauma. +b. Severe bleeding and hemodynamic instability, excessive mucosa/ bleed. These patients should be treated with blood transfusion and monitoring. There is little evidence to support the practice of transfusing platelet concentrates and/or fresh-frozen plasma for severe bleeding. When bleeding cannot be managed with fresh whole blood or fresh-packed cells and there is possibility of DIC, fresh-frozen plasma and platelet rich plasma may be considered. +Management of fluid overload +Fluid overload with stable haemodynamic status and is out of the critical phase (more than 24-48 hr of defervescence). In such patients stop intravenous fluids but continue close moni­ toring. If necessary, give oral or intravenous furosemide 0.1-0.5 mg/kg/dose once or twice daily, or a continuous infusion of furosemide 0.1 mg/kg/hr. Monitor serum potassium and correct the ensuing hypokalemia. + +Fluid overload with stable haemodynamic status but is still within the critical phase. Reduce the intravenous fluid accordingly. Avoid diuretics during the plasma leakage phase because they may lead to intravascular volume depletion. Patients with fluid overload and hypotension with low or normal hematocrit levels may have occult hemorrhage. Further infusion of large volumes of intravenous fluids will lead to a poor outcome. Careful fresh whole blood transfusion should be initiated as soon as possible. If the patient remains in shock and the hematocrit is elevated, repeated small boluses of a colloid solution may help. +Other supportive care Other organ dysfunction (liver, kidney) should be managed. There is no therapeutic utility of corticosteroids, intravenous immunoglobulins or recombinant activated factor VIL Broad spectrum anti­ biotics are only indicated in case of superadded bacterial infection. Blood transfusion (20 ml/kg) is indicated when shock persists despite declining hematocrit values (which are indicative of adequate fluid replacement) due to overt or internal hemorrhage. +All children with hypotension should receive oxygen inhalation by nasal cannula, face mask or oxygen hood. + +Monitoring +In view of the dramatic course of severe dengue, monitoring of the patient is crucial in the first few hour of +__ _s_s_e_n_t.ia•l•P•ae_•t_r.d-ici _________________________________ +_s +E + +Severe dengue fever + +[A�ssmet° of shock + + + +Hypotension + +loss 1111 +�+ +.. + +Ringer lactate (RL) 10-20 ml/kg/hr] +,-- + + +c"ord� blood pressure j ++ + +DSSIV + +Ringer lactate 20 ml/kg bolus; up to 3 boluses +1 +--- +• Assessment --------- � + + + + + + +Gradually decrease +-r +.� +Ringer lactate infusion with monitoring as in Fig. 10.9 + + + + +Improved + +�Noimp� + +�ocrit increased <14------' Hematocrit !ecreasedj 1 -- T +J +• +-' +'t +I +-.. +'t +Colloids 10 ml/kg [Blood transfusio� +I + +f As;;sment 4 +1 +I + +� improvemet] + +Look for anemia, acidosis, myocardial dysfunction; treat accordingly + + +Fig. 10.10: Algorithm for management of severe dengue fever. DSS dengue shock syndrome + + +illness. Heart rate, respiratory rate, blood pressure and pulse pressure should be monitored every 30 min till the patient is stable, thereafter every 2-4 hr should be +continued as long as the child is in the hospital. In critically ill children, central venous pressure and accurate urine output with an indwelling urinary catheter should be monitored. Absolute platelet counts should be checked once a day till it shows a rising trend. + +Prognosis +Dengue fever is a self-limited disease but the mortality in severe dengue may be as high as 20-30% if left untreated. +Early recognition of illness, careful monitoring and appropriate fluid therapy alone has resulted in consi­ derable reduction of case fatality rate to less than 1 percent. Early recognition of shock is of paramount importance as the outcome of a patient with DSS depends on the duration of shock. If shock is identified when pulse pressure starts getting narrow and intravenous fluids are administered at this stage, the outcome is excellent. + +Prevention +Preventive measures are directed towards elimination of adult mosquitoes and their larvae. During epidemics aerial spraying or fogging with malathion is recommended for control of adult mosquitoes. However, larval control +measures by source reduction and use of larvicides are even + +more crucial. Aedes aegypti mosquitoes breed in and around human dwellings and flourish in fresh water. Special drives should be launched during and soon after the rainy season to interrupt breeding cycle of mosquitoes. There should be no opportunity for stagnation of water in the bathroom, kitchen, terrace, lawn and other open places. The stored water should be kept covered. Cooperation from every house owner and public establishment is crucial for the success of control program. Strong motivation and commitment on the part of govenment and its employees are fundamental pre­ +requisites for the success of control measures. +Mesocyclops, the shellfish are credited to eat and effectively eliminate larvae of Aedes aegypti. The strategy has been used with success by Australian scientists +working in Vietnam by growing shellfish in ponds and water traps. A live attenuated quadruple vaccine is undergoing clinical trials but there are concerns whether vaccine may predispose to development of severe dengue. + +Suggested Reading +Anonymous. Dengue Guidelines for Diagnosis, Treatment, Prevention and Control. A joint publication of the World Health Organization (WHO) and the Special Programme for Research and Training in Tropical Diseases (TOR), 2009 +Kabra SK, Jain Y, Pandey RM, et al. Dengue hemorrhagic fever in children in the 1996 Delhi epidemic. Trans Royal Society Trop Med Hygiene 1999;93:29-8 +Infections and Infestations - + + +Kabra SK, Lodha R, Singha! T. Dengue infections. In Medical Emergencies in ChjJdren, 5th ed, Singh M (Ed), New Delhi, Sagar Publications, 2012 +Kabra SK, Jain Y, Singha! T, Ratageri VH. Dengue hemorrhagic fever: clirucal manifestations and management. Indian J Pediatr 1999;66: 93-101 + +Chikungunya +Chikungunya is an acute disease, which results in fever, arthritis and skin rash, caused by an enveloped virus capable of replicating in mosquitoes. Because of severe arthritic symptoms, the disease is given the Swahili name of chikungunya (that which bends up). Since an outbreak of chikungunya in Tanzania in 1952, large epidemics were reported in South Africa, India (1971), South-East Asia and Philippines. Re-emergence of chikungunya disease occurred in India during 2005-06, causing 1.3 million cases in 13 states, chiefly Andhra Pradesh and Karnataka. + +Epidemiology +The rural cycle of chikungunya transmission involves Aedes africans, A. fancifer and wild primates, while the urban cycle involves A. aegypti and humans. In rural cycle (seen in Africa) the disease is endemic with a small number of cases occurring in most year. In urban areas, the out­ breaks are sporadic and explosive with infection of a large population within weeks. In Asia, the virus may be main­ tained in urban cycle, with A. aegypti, or require reinocu­ lation before onset of epidemic. Outbreaks typically occur during the rainy season, associated with the population density of the mosquito vector, which breeds in household containers and puddles with peak activity in mid-moing and late afternoon. After an epidemic, the disease typically vanishes for year, because a large proportion of the population is immune. + +Clinical Features +The disease has a sudden onset, with an incubation period of 2-12 days. Infection is characterized by fever, headache, fatigue, nausea, vomiting, muscle pain, rash and joint pain. Fever rises abruptly to 103-104°F and is accompanied by rigors. The acute phase lasts for 2-3 days. Joint pain appears suddenly and is often very severe in intensity; the arthralgia/ arthritis is polyarticular, migratory and predominantly affects the small joints of hands, wrist, ankle and feet, with less involvement of larger joints. Headache is present in 80% of cases. Photophobia and retro-orbital pain may also occur. An itchy, transient maculopapular rash appears 4-8 days later affecting the trunk and limbs. Inguinal lymph nodes may be enlarged. The joint pains may continue for many months after the illness. Fatalities are rare and associated with young age, thrombocytopenia and shock. Rarely encephalopathy may occur in infants and young children. + +Diagnosis +Chikungunya should be suspected in patients who presents with the characteristic triad of fever, rash and arthritis. Viremia is present in most patients during the initial 2-4 days of disease and may be isolated in cell +cultures. Polymerase chain reaction can be used to confirm +the infection. Virus specific IgM antibodies may be detected by capture ELISA and hemagglutination inhibition assays by 5-7 days of illness. + +Treatment +No specific treatment is available. Symptomatic treatment in the form of rest, fluids and ibuprofen, naproxen, acetaminophen, or paracetamol may relieve symptoms. Aspirin should be avoided during acute phase of illness. + +Prevention and Control +Strategies for prevention and control include breaking the transmission cycle of A. aegypti and by holding the mosquito population at extremely low levels. A live attenuated vaccine that induces longterm production of neutralizing antibodies, is being examined. + +Suggested Reading +Griffin DE. Alphaviruses. In: Krupe DM, Howley PM. Fields Virology, 5th edn. Philadelphla: Lippincott Williams & Wilkins 2007:1047-8 +Guidelines on clirucal management of chikungunya fever. WHO 2008 Sebastian MR, Lodha R, Kabra SK. Chikungunya infection in children. +Indian J Pediatrics 2009;76:185-9 + +HUMAN IMMUNODEFICIENCY VIRUS (HIV) +HIV infection has become an important contributor to childhood morbidity and mortality, especially in many developing countries. The World Health Organization (WHO) estimated that 34 million persons worldwide were living with HIV infection at the end of 2011; 2.5 million of these were children under 15 yr of age. More than 90% of HIV-infected individuals live in developing nations. Sub­ Saharan Africa accounts for nearly 90% of the world's total population of HIV-infected children. India and Thailand dominate the epidemic in South-East Asia, with more recent expansion into Vietnam, China and Cambodia. +Worldwide, it is estimated that nearly 2 million require antiretroviral treatment. At present only 25% of such children have an access to the antiretroviral therapy. Without access to antiretroviral therapy, 20% of vertically infected children will progress to the acquired immuno­ deficiency syndrome (AIDS) or death in their first yr of life and more than half of HIV-infected children will die before their fifth birthday. + +HIV-1 and HIV-2. HIV-1 and HIV-2 are members of the Retroviridae family and belong to the Lentivirus genus. The HIV-1 genome is single-stranded RNA that is 9.2 kb in size. The genome has three major sections: the gag region, which encodes the viral core proteins (p24, pl7, +---E•s•s•e•n•t-ia•l•P-e.d.ia.t.ri•cs•---------------------------------- + + +p9, p6; these are derived from the precursor p55), the pol region, which encodes the viral enzymes (reverse transcriptase [p51], protease [plO], and integrase [p32]); and the env region, which encodes the viral envelope proteins (gp120 and gp41). +The major external viral protein of HIV-1 is a heavily glycosylated gp120 protein which contains the binding site for the CD4 molecule, the most common T lymphocyte +surface receptor for HIV. Most HIV strains have a specific tropism for one of the chemokines: the fusion-inducing molecule, CXCR-4, which has been shown to act as a co­ receptor for HIV attachment to lymphocytes, and CCR-5, a � chemokine receptor that facilitates HIV entry into macrophages. +Following viral attachment, gp120 and the CD4 molecule undergo conformational changes, allowing gp41 to interact with the fusion receptor on the cell surface. Viral fusion with the cell membrane allows entry of viral RNA into the cell cytoplasm. Viral DNA copies are then trans­ cribed from the virion RNA through viral reverse transcriptase enzyme activity and duplication of the DNA copies produces double-stranded circular DNA. Because the HIV-1 reverse transcriptase is error-prone, many mutations arise, creating wide genetic variation in HIV-1 isolates even within an individual patient. The circular DNA is transported into the cell nucleus where it is integrated into chromosomal DNA; this is called as the provirus. The provirus can remain dormant for extended periods. +HIV-1 transcription is followed by translation. A capsid polyprotein is cleaved to produce, among other products, the virus-specific protease (plO). This enzyme is critical for HIV-1 assembly. The RNA genome is then incorporated into the newly formed viral capsid. As the new virus is formed, it buds through the cell membrane and is released. HIV-2 is a rare cause of infection in children. It is most prevalent in Western and Southern Africa. If HIV-2 is suspected, a specific test that detects antibody to HIV-2 +peptides should be used. + +Transmission. Transmission of HIV-1 occurs via sexual contact, parenteral exposure to blood, or vertical transmission from mother to child. The primary route of infection in the pediatric population is vertical transmission. Most large studies in the United States and Europe have documented mother-to-child transmission rates in untreated women between 12 and 30%. In contrast, transmission rates in Africa and Asia are higher, up to 50%. +Vertical transmission of HIV can occur during the intrauterine or intrapartum periods, or through breast­ feeding. Up to 30% of infected newborns are infected in utero. The highest percentages of HIV-infected children acquire the virus intrapartum. Breastfeeding is an important route of transmission, especially in the developing countries. The risk factors for vertical transmission include pre term delivery ( <34 week + + +gestation), a low maternal antenatal CD4 count, use of illicit drugs during pregnancy, >4 hr duration of ruptured membranes and birthweight <2500 g. +Transfusions of infected blood or blood products have accounted for a variable proportion of all pediatric AIDS cases. Heat treatment of factor VIII concentrate and HIV antibody screening of donors has virtually eliminated HIV transmission to children with hemophilia. Blood donor screening has dramatically reduced, but not eliminated, the risk of transfusion-associated HIV infection. Sexual contact is a major route of transmission in the adolescent population. + +Natural History +Before highly active antiretroviral therapy (HAART) was available, three distinct patterns of disease were described in children. Approximately 10-20% of HIV-infected newborns in developed countries presented with a rapid disease course, with onset of AIDS and symptoms during the first few months of life and, if untreated, death from AIDS-related complications by 4 yr of age. In resource­ poor countries, >85% of the HIV-infected newborns may have such a rapidly progressing disease. +It has been suggested that if intrauterine infection coincides with the period of rapid expansion of CD4 cells in the fetus, it could effectively infect the majority of the body's immunocompetent cells. Most children in this group have a positive HIV-1 culture and/or detectable virus in the plasma in the first 48 hr of life. This early evidence of viral presence suggests that the newborn was infected in utero. In contrast to the viral load in adults, the viral load in infants stays high for at least the first 2 yr of life. +The majority of perinatally infected newborns (60-80%) present with a second pattern-that of a much slower progression of disease with a median survival time of 6 yr. Many patients in this group have a negative viral culture or PCR in the 1st week of life and are therefore considered to be infected intrapartum. In a typical patient, the viral load rapidly increases by 2-3 months of age (median 100,000 copies/ml) and then slowly declines over a period of 24 months. This observation can be explained partially by the immaturity of the immune system in newborns and infants. The third pattern of disease (i.e. longterm survivors) occurs in a small percentage ( <5%) of perinatally infected children who have minimal or no progression of disease with relatively normal CD4 counts and very low viral loads for longer than 8 yr. +HIV-infected children have changes in the immune system that are similar to those in HIV-infected adults. CD4 cell depletion may be less dramatic because infants normally have a relative lymphocytosis. Therefore, for example, a value of 1,500 CD4 cells/mm3 in children <1 yr of age is indicative of severe CD4 depletion and is comparable to <200 CD4 cells/ mm3 in adults. Lymphopenia is relatively rare in perinatally infected children and is +Infections and Infestations - + + + +usually only seen in older children or those with endstage disease. +B cell activation occurs in most children early in the infection as evidenced by hypergammaglobulinemia associated with high levels of anti-HIV-1 antibody. This response may reflect both dysregulation of T cell suppression of B-cell antibody synthesis and active CD4 enhancement of B-lymphocyte humoral responses. +CD4 depletion and inadequate antibody responses lead to increased susceptibility to various infections and the clinical manifestations vary with the severity of immuno­ deficiency. + +Clinical Manifestations +The clinical manifestations of HIV infection vary widely among infants, children and adolescents. In most infants, physical examination at birth is normal. Initial signs and symptoms may be subtle and nonspecific, such as lymphadenopathy, hepatosplenomegaly, failure to thrive, chronic or recurrent diarrhea, interstitial pneumonia, or oral thrush and may be distinguishable from other causes only by their persistence. Whereas systemic and pulmonary findings are common in the United States and Europe, chronic diarrhea, wasting and severe malnutrition predominate in Africa. Symptoms found more commonly in children than adults with HIV infection include recurrent bacterial infections, chronic parotid swelling, lymphocytic interstitial pneumonitis and early onset of progressive neurologic deterioration. +The pediatric HIV disease is staged by using two parameters: clinical status (Table 10.4) and degree of immunologic impairment (Table 10.5). + +Opportunistic Infections +Children with HIV infection and advanced or severe immunosuppression are susceptible to develop various opportunistic infections. The important pathogens include Pneumocystis jiroveci, Cryptosporidium, Cryptococcus, Isospora and CMV. + +Respiratory Diseases +Pneumocystis pneumonia Pneumocystis jiroveci (pre­ viously P. carinii) pneumonia (PCP) is the opportunistic infection that led to the initial description of AIDS. PCP is one of the commonest AIDS defining illnesses in children in the US and Europe. However, data regarding the incidence of PCP in children in other parts of the world are scarce. The majority of the cases occur between 3rd and 6th months of life. +Even if a child develops PCP while on prophylaxis, therapy may be started with cotrimoxazole. This is because the prophylaxis may have failed because of poor compliance, or unusual pharmacokinetics. Untreated, PCP is universally fatal. With the use of appropriate therapy, the mortality decreases to less than 10%. The risk factors + + +for mortality are the severity of the episode and the severity of the immunosuppression. +Recurrent bacterial infections In various studies from developing countries, up to 90% of HIV-infected children had history of recurrent pneumonias. Initial episodes of pneumonia often occur before the development of significant immunosupression. As the immunosupression increases the frequency increases. +The common pathogens for community-acquired pneumonia in these children are Streptococcus pneumoniae, Haemophilus influenzae and Staphylococcus aureus. However, in children with severe immunosuppression and in hospital-acquired infections, gram-negative organisms, such as, Pseudomonas aeruginosa gain importance. +The clinical features of pneumonia in HIV-infected children are similar to those in uninfected children. However, in severely immunocompromised children, the signs may be subtle. Often, the response to therapy is slow and the relapse rates are high. Bacteremia may be more common, seen in up to 50%. +Choices of appropriate antibiotics are often made based on local patterns of etiologies and susceptibilities. In many settings, an appropriate choice would be a combination of a broad spectrum cephalosporin and an inoglycoside. In areas where a large proportion of Staphylococcus aureus isolates are resistant to antistaphylococcal antibiotics, then the empiric inclusion of vancomycin, clindamycin, linezolid should be considered. Children with nonsevere pneumonia can be managed as outpatients using a second or a third generation cephalosporin or a combination like amoxicillin-clauvulinic acid. Since Pneumocystis jiroveci pneumonia cannot be excluded at the outset in most HIV­ infected children with severe respiratory infections, co­ trimoxazole should be added unless another diagnosis has been definitively made. +The principles of supportive care of HIV-infected children admitted with severe pneumonia are similar to those in non-HIV-infected children. +Tuberculosis With the spread of the HIV infection, there has been resurgence in tuberculosis. Coexistent TB and HIV infections accelerate the progression of both the diseases. HIV infected children are more likely to have extra­ pulmonary and disseminated tuberculosis; the course is also likely to be more rapid. An HIV infected child with tubercular infection is more likely to develop the disease than a child without HIV infection. The overall risk of active TB in children infected with HIV is at least 5- to 10-fold higher than that in children not infected with HIV. +All HIV-infected children with active TB should receive longer duration of antitubercular therapy. A 9-12 month therapy is preferred. A close followup is essential to diagnose nonresponse/ drug resistance early. +Viral infections Infections caused by respiratory syncytial virus, influenza and parainfluenza viruses result in +_ E_s_s_.en.t.ia•l•P•ed • a.t.ri•cs---------------------------------- +• +- +i +_ + +Table 10.4: WHO clinical staging of HIV/AIDS in children with confirmed infection +Clinical stage 1 +Asymptomatic +Persistent generalized lymphadenopathy +Clinical stage 2 +Unexplained• persistent hepatosplenomegaly Papular pruritic eruptions +Fungal nail infection +Angular cheilitis +Lineal gingival erythema Extensive wart virus infection Extensive molluscum contagiosum Recurrent oral ulceration +Unexplained• persistent parotid enlargement Herpes zoster +Recurrent or chronic upper respiratory tract infections (otitis media, otorrhea, sinusitis, tonsillitis) +Clinical stage 3 +Unexplained• moderate malnutrition or wasting not adequately responding to standard therapy Unexplained• persistent diarrhea (14 days or more) +Unexplained• persistent fever (above 37.5°C intermittent or constant, for longer than one month) Persistent oral candidiasis (after the first 6-8 weeks of life) +Oral hairy leukoplakia +Acute necrotizing ulcerative gingivitis/periodontitis Lymph node tuberculosis +Pulmonary tuberculosis +Severe recurrent bacterial pneumonia Symptomatic lymphoid interstitial pneumonitis +Chronic HIV-associated lung disease including bronchiectasis +Unexplained anemia ( <8 g/ dl), neutropenia ( <0.5 x 109 /1) or chronic thrombocytopenia ( <50 x 109/1). +Clinical stage 4b +Unexplained• severe wasting, stunting or severe malnutrition not responding to standard therapy Pneumocystis pneumonia +Recurrent severe bacterial infections (e.g. empyema, pyomyositis, bone or joint infection, meningitis, but excluding pneumonia) Chronic herpes simplex infection (orolabial or cutaneous of more than one month's duration or visceral at any site) +Esophageal candidiasis (or candidiasis of trachea, bronchi or lungs) Extra pulmonary/ disseminated TB +Kaposi sarcoma +Cytomegalovirus infection: retinitis or CMV infection affecting another organ, with onset at age > 1 mo Central nervous system toxoplasmosis (after one month of life) +Extrapulmonary cryptococcosis (including meningitis) HIV encephalopathy +Disseminated endemic mycosis (extrapulmonary histoplasmosis, coccidioidomycosis) Disseminated nontuberculous mycobacterial infection +Chronic cryptosporidiosis (with diarrhea) Chronic isosporiasis +Cerebral or B cell non-Hodgkin lymphoma Progressive multifocal leukoencephalopathy +Symptomatic HIV-associated nephropathy or HIV-associated cardiomyopathy + +•unexplained refers to where the condition is not explained by other causes +bSome additional specific conditions can also be included in regional classifications, e.g. reactivation of American trypanosomiasis (meningoencephalihs and/or myocardihs) in Americas region, penicilliosis in Asia and HIV-associated rectovaginal fistula in Africa + + +symptomatic disease more often in HIV infected children in comparison to noninfected children. Infections with other viruses such as adenovirus and measles virus are more likely to lead to serious sequelae than with the + + +previously mentioned viruses. As RSV infection most often occurs in children in the first 2 yr of life, during which many of these may not be severely immunocompromised, the severity of illness may not be different from the non- +Infections and Infestations - + + +Table 10.5: Severity of immune suppression based on CD4 levels children + +HIV-associated immunodeficiency +Not significant (normal) Mild +Advanced Severe + + +'11 mo >35% 30-35% 25 -30% +<25% or +<1500 cells/mm3 + + +Age-related CD4+ cell values +12-35 mo 36-59 mo +>30% >25% 25-30% 20-25% 20-25% 15-20% +<20% or <15% or +<750 cells/mm3 <350 cells/mm3 + + +�5 yr +>500 cells/mm3 +35-499 cells/mm3 200-349 cells/mm3 +<200 cells/mm3 or <15% + + + +HIV infected children. In children with AIDS, dissemi­ nated CMV is a known opportunistic infection, but pneumonia caused by this virus is rare. The principles of diagnosis and treatment of these infections in HIV-infected children are similar to those in non-HIV infected children. +Fungal infections Pulmonary fungal infections usually present as a part of disseminated disease in immuno­ compromised children. Primary pulmonary fungal infec­ tions are uncommon. +Pulmonary candidiasis should be suspected in any sick HIV-infected child with lower respiratory tract infection that does not respond to the common therapeutic modali­ ties. A positive blood culture supports the diagnosis of invasive candidiasis. + +Lymphoid interstitial pneumonitis (LIP) LIP has been recognized as a distinctive marker for pediatric HIV infection and is included as a Class B conditio11 in the revised CDC criteria for AIDS in children. In absence of antiretroviral therapy, nearly 20% of HIV-infected children developed LIP. +The etiology and pathogenesis of LIP are not well understood. Suggested etiologies include: an exaggerated immunologic response to inhaled or circulating antigens, and/or primary infection of the lung with HIV, Epstein­ Barr virus (EBV), or both. +LIP is characterized by nodule formation and diffuse infiltration of the alveolar septae by lymphocytes, plasmacytoid lymphocytes, plasma cells and immunoblasts. There is no involvement of the blood vessels or destruction of the lung tissue. Children with LIP have a relatively good prognosis compared to other children who meet the surveillance definition of AIDS. +LIP is usually diagnosed in children with perinatally acquired HIV infection when they are older than 1 yr of age, unlike PCP. Most children with LIP are asymptomatic. Tachypnea, cough, wheezing and hypoxemia may be seen when children present with more severe manifestations; crepitations are uncommon. Clubbing is often present in advanced disease. These patients can progress to chronic respiratory failure. Long standing LIP may be associated with chronic bronchiectasis. The presence of a reticulo­ nodular pattern, with or without hilar lymphadenopathy, that persists on chest radiograph for 2 months or greater and that is unresponsive to antimicrobial therapy is considered presumptive evidence of LIP. Care should be + +taken to exclude other possible etiologies. A definitive diagnosis of LIP can only be made by histopathology. +Early disease is managed conservatively. The effect of antiretrovirals on LIP is probably limited. Steroids are indicated if children with LIP have symptoms and signs +of chronic pulmonary disease, clubbing and/ or hypoxemia. +Treatment usually includes an initial 4 to 12 week course of prednisolone (2 mg/kg/day) followed by a tapering dose, using oxygen saturation and clinical status as a guide to improvement. This is then followed by chronic low dose prednisolone. + +Gastrointestinal Diseases +The pathologic changes in the gastrointestinal tract of children with AIDS are variable and can be clinically significant. +A variety of microbes can cause gastrointestinal disease, including bacteria (salmonella, campylobacter, Myca­ bacterium avium intracellulare complex), protozoa (giardia, cryptosporidium, isospora, microsporidia), viruses (CMV, HSV, rotavirus) and fungi (Candida). The protozoa! infections are most severe and can be protracted in children with severe immunosuppression. Children with cryptosporidium infestation can have severe diarrhea +leading to hypovolemic shock. AIDS enteropathy, a syn­ +drome of malabsorption with partial villous atrophy not associated with a specific pathogen, is probably the result of direct HIV infection of the gut. +Chronic liver inflammation is relatively common in HIV infected children. In some children, hepatitis caused by CMV, hepatitis B or C viruses, or mycobacteria may lead to liver failure and portal hypertension. It is important to recognize that several of the antiretroviral drugs such as didanosine and protease inhibitors may also cause reversible elevation of transaminases. +Pancreatitis is uncommon in HIV infected children. This may be the result of drug therapy, e.g. didanosine, lami­ vudine, nevirapine, or pentnidine. Rarely, opportunistic infections such as mycobacteria or CMV may be responsi­ ble for acute pancreatitis. +The principles of management of these conditions are similar to those in non-HIV-infected children. + +Neurologic Diseases +The incidence of central nervous system involvement in perinatally infected children may be more than 50% in +- •Es•se.la•P-ed•i a•tri•c• ------------------------------ +s +-- +.•nt +i +- + + +developing countries but lower in developed countries, with a median onset at about one and a half yr of age. The most common presentation is progressive encephalopathy with loss or plateau of developmental milestones, cognitive deterioration, impaired brain growth resulting in acquired microcephaly and symmetric motor dys­ function. Meningitis due to bacterial pathogens, fungi such as Cryptococcus and a number of viruses may be responsible. Toxoplasmosis of the nervous system is exceedingly rare in young infants, but may occur in HIV­ infected adolescents; the overwhelming majority of these cases have serum IgG antitoxoplasma antibodies as a marker of infection. The management of these conditions is similar to that in non-HIV-infected children; the response rates and outcomes may be poorer. + +Cardiovascular Involvement +Cardiac abnormalities in HIV-infected children are common, persistent and often progressive; however, the majority of these are subclinical. Left ventricular structure and function progressively may deteriorate in the first 3 yr of life, resulting in increased ventricular mass in HIV­ infected children. Children with encephalopathy or other AIDS-defining conditions have the highest rate of adverse cardiac outcomes. Resting sinus tachycardia has been reported in up to nearly two-thirds and marked sinus arrhythmia in one-fifth of HIV-infected children. Gallop rhythm with tachypnea and hepatosplenomegaly appear to be the best clinical indicators of congestive heart failure. Electrocardiography and echocardiography are helpful in assessing cardiac function before the onset of clinical symptoms. + +Renal Involvement +Nephropathy is an unusual presenting symptom of HIV infection, more commonly occurring in older symptomatic children. Nephrotic syndrome is the most common manifestation of pediatric renal disease, with azotemia and normal blood pressure. Polyuria, oliguria and hematuria have also been observed in some patients. + +Diagnosis +All infants born to HIV-infected mothers test antibody­ positive at birth because of passive transfer of maternal HIV antibody across the placenta. Most uninfected infants lose maternal antibody between 6 and 12 months of age. As a small proportion of uninfected infants continue to have maternal HIV antibody in the blood up to 18 months of age, positive IgG antibody tests cannot be used to make a definitive diagnosis of HIV infection in infants younger than this age. In a child older than 18 months of age, demonstration of IgG antibody to HIV by a repeatedly reactive enzyme immunoassay (EIA) and confirmatory test (e.g. Western blot or immunofluorescence assay) can establish the diagnosis of HIV infection. Although serologic diagnostic tests were the most commonly used + + +in the past, tests that allow for earlier definitive diagnosis in children have replaced antibody assays as the tests of choice for the diagnosis of HIV infection in infants. +Specific viral diagnostic assays, such as HIV DNA or RNA PCR, HIV culture, or HIV p24 antigen immune dissociated p24 (ICD-p24), are essential for diagnosis of young infants born to HIV infected mothers. By 6 months of age, the HIV culture and/or PCR identifies all infected infants, who are not having any continued exposure due to breast feeding. HIV DNA PCR is the preferred virologic assay in developed countries. Plasma HIV RNA assays may be more sensitive than DNA PCR for early diagnosis, but data are limited. HIV culture has similar sensitivity to HIV DNA PCR; however, it is more technically complex and expensive and results are often not available for 2--4 week compared to 2-3 days with PCR. The p24 antigen assay is less sensitive than the other virologic tests. Figure 10.11 shows the suggested algorithm for diagnosis of HIV infection in infants. The national program (Early Infant Diagnosis) now uses HIV DNA PCR test on dried blood spot samples; the positive tests need confirmation using a HIV DNA PCR on a whole blood sample. + +Management +The management of HIV infected child includes antiretro­ viral therapy, prophylaxis and treatment of opportunistic infections and common infections, adequate nutrition and immunization. + +Antiretroviral Therapy +Decisions about antiretroviral therapy for pediatric HIV­ infected patients are based on the magnitude of viral replication (i.e. viral load), CD4 lymphocyte count or percentage and clinical condition. A child who has WHO stage 3 or 4 clinical disease should receive ART irrespective of the immunologic stage. Children who are asymptomatic or have stage 1 or 2 disease may be started on ART if they have evidence of advanced or severe immunosupression. However, current evidence shows that young children less than 2 yr of age have a higher risk of mortality without ART. The World Health Organization now recommends initiation of ART for all HIV infected children less than 2 yr age irrespective of clinical symptoms and the immunologic stage. +Availability of antiretroviral therapy has transformed HIV infection from a uniformly fatal condition to a chronic infection, where children can lead a near normal life. The currently available therapy does not eradicate the virus and cure the child; it rather suppresses the virus replication for extended periods of time. The 3 main groups of drugs are nucleoside reverse transcriptase inhibitors (NRTI), non­ nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI). Highly active antiretroviral therapy (HAART) is a combination of 2 NRTis with a PI or a NNRTI. The national program for management of HIV infected children recommends a combination of zidovudine, lamivudine and nevi.rapine as the first line therapy. The +Infections and Infestations - +Delivery + + + +HIV-infected pregnant woman + + + + +ie +Repeat HIV DNA PCR] to confirm +_J + +HIV-exposed infant (breastfed and nonbreastfed) + + + +First HIV DNA PCR I +J�::�· + + +Symptomatic HIV-exposed child <18 months of age (not previously diagnosed) + + +8 l +C +;;ative � PCR tes� + + + + +G 8 + + +Second PCR after 6-8 weeks I of stopping breastfeeding or +I +earlier if symptomatic _J + +G 8 + + + + +s;cond PCR at 6 months to confirm status +l +J +l +I + + + +Repeat test and refer for followup + +Report HIV negative + + +Repeat test and refer for followup + + +Fig. 10.11: Diagnosis of infection with HIV in children <18 months. If child is >18-month-old, adult testing strategies may be used + + +alternative regimen is a combination of stavudine, lamivudine and nevirapine. The details of the anti­ retroviral drugs are shown in Table 10.6. Pediatric fixed dose combinations have been developed, and these are administered using a weight-band based dosing system (NACO guidelines). + +Corimoxazole Prophylaxis +In resource-limited settings, cotrimoxazole prophylaxis is recommended for all HIV exposed infants starting at 4-6 weeks of age and continued until HIV infection can be excluded. Cotrimoxazole is also recommended for HIV­ exposed breastfeeding children of any age and cotrimo­ xazole prophylaxis should be continued until HIV infection can be excluded by HIV antibody testing (beyond 18 months of age) or virological testing (before 18 months of age) at least six weeks after complete cessation of breastfeeding. +All children younger than one yr of age documented to be living with HIV should receive cotrimoxazole pro­ phylaxis regardless of symptoms or CD4 percentage. After one yr of age, initiation of cotrimoxazole prophylaxis is recommended for symptomatic children (WHO clinical stages 2, 3 or 4 for HIV disease) or children with CD4 <25%. All children who begin cotrimoxazole prophylaxis (irrespective of whether cotrimoxazole was initiated in the first yr of life or after that) should continue until the age of five yr, when they can be reassessed. +Nutrition +It is important to provide adequate nutrition to HIV­ infected children. Many of these children have failure to + +thrive. These children will need nutritional rehabilitation. In addition, micronutrients like zinc may be useful. + +Immunization +The vaccines that are recommended in the national schedule can be administered to HIV infected children except that symptomatic HIV infected children should not be given the oral polio and BCG vaccines. + +Prevention of Mother to Child Transmission (PMTCT) +The risk of MTCT can be reduced to under 2% by interventions that include antiretroviral (ARV) prophylaxis given to women during pregnancy and labor and to the infant in the first weeks of life, obstetrical interventions including elective cesarean delivery (prior to the onset of labor and rupture of membranes) and complete avoidance of breastfeeding. +Antiretroviral drug regimens for treating pregnant +women For HIV-infected pregnant women in need of ART for their own health, ART should be administered irrespective of gestational age and is continued through­ out pregnancy, delivery and thereafter (recommended for all HIV-infected pregnant women with CD4 cell count <350 cells/mm3, irrespective of WHO clinical staging; and for WHO clinical stage 3 or 4, irrespective of CD4 cell count). +Recommended regimen for pregnant women with indication for ART is combination of zidovudine (AZT), lamivudine (3TC) and nevirapine (NVP) or efavirenz (EFV) during antepartum, intrapartum and postpartum +--E•s•s•e•n.ti•Ia•.ed•i•a.tr.ic•s ------------------------------- +.P +- + +Table 10.6: Commonly used antiretroviral drugs in children Drug Dose Side effects +Nucleoside reverse transcriptase inhibitors + +Abacavir (ABC) + +Didanosine + + + + + +Lamivudine (3TC) + + +Stavudine (d4T) + + +Zalcitabine + +Zidovudine (AZT) + +3 mo-13 yr: 8 mg/kg/dose q 12 hr +>13 yr: 300 mg/dose q 12 hr (max 300 mg/dose) 0-3 mo: 50 mg/m2/dose q 12 hr +3 mo-13 yr: 90-150 mg/m2 q 12 hr (max 200 mg/dose) +> 13 yr and <60 kg: 125 mg tablets q 12 hr +> 13 yr and >60 kg: 200 mg tablet q 12 hr (higher dose for powder preparations) +1 mo-13 yr: 4 mg/kg q 12 hr +>13 yr and <50 kg: 4 mg/kg/dose q 12 hr >13 yr and >50 kg: 150 mg/dose q 12 hr 1 mo-13 yr: 1 mg/kg q 12 hr +>13 yr and 30-60 kg: 30 mg/dose q 12 hr >13 yr and >60 kg: 40 mg/dose q 12 hr <13 yr: 0.01 mg/kg/dose q 8 hr +>13 yr: 0.75 mg q 8 hr Neonates: 4 mg/kg BD +3 mo-13 yr: 90-180 mg/m2 q --8 hr >13 yr: 300 mg q 12 hr + + +Hypersensitivity +Peripheral neuropathy, pancreatitis, abdominal pain, diarrhea + + + + +Pancreatitis, neuropathy, neutropenia + + +Headache, GI upset, neuropathy + + +Rash, peripheral neuropathy, pancreatitis + +Anemia, myopathy + +Non-nucleoside reverse transcriptase inhibitors + +Nevirapine (NVP) + + + +Efavirenz (EFV) + +2 mo-13 yr: 120 mg/m2 (max 200 mg) q 24 hr for 14 days, followed by 150-200 mg/m2 q 12 hr +>13 yr: 200 mg q 24 hr for 14 days, then increase to 200 mg q 12 hr if no rash or other side effects +>3 yr: 10-14.9 kg: 200 mg q 24 hr 15-19.9 kg: 250 mg q 24 hr +20-24.9kg: 300 mg q 24 hr 25-32.4 kg: 350 mg q 24 hr 32.5-39.9 kg: 400 mg q 24 hr �40 kg: 600 mg q 24 hr + + +Skin rash, Stevens-Johnson syndrome + + + +Skin rash, CNS symptoms, increased transaminase levels + +Protease inhibitors + +Amprenavir + + +Indinavir +Lopinavir/(LPV) ritonavir + + + + +Nelfinavir + +Ritonavir + + +Saquinavir + + +4-16 yr and <50 kg: 22.5 mg/kg q 12 hr (oral solution) or 20 mg/kg q 12 hr (capsules) +>13 yr and >50 kg: 1200 mg q 12 hr (capsules) 500 mg/m2 q 8 hr; >13 yr: 800 mg q 8 hr +6 mo-12 yr: 7-<15 kg: 12 mg/kg lopinavir/ +3 mg/kg ritonavir q 12 hr with food; 15-40 kg: 10 mg/kg lopinavir/2.5 mg/kg ritonavir q +12 hr with food +>12 yr: 400 mg lopinavir/100 mg ritonavir q 12 hr with food +<13 yr: 50-55 mg/kg q 12 hr +> 13 yr: 1250 mg q 12 hr (max 2000 mg) +<13 yr: 350-400 mg/m2 q 12 hr (starting dose: 250 mg/m2) +> 13 yr: 600 mg q 12 hr (starting with 300 mg) +50 mg/kg q 8 hr; > 13 yr: soft gel capsules-1200 mg q 8 hr + + + + +Hyperbilirubinemia, nephrolithiasis +Diarrhea, fatigue, headache, nausea; increased cholesterol and triglycerides + + + + +Diarrhea, abdominal pain + +Bad taste, vomiting, nausea, diarrhea, rarely, hepatitis + +Diarrhea, headache, skin rash +Infections and Infestations - + + + +period; EFV-based regimens should not be newly-initiated during the first trimester of pregnancy. +Recommended regimen for pregnant women who are not eligible for ART for their own health, but for preventing MTCT is to start ART as early as 14 weeks gestation or as soon as possible when women present late in pregnancy, in labor or at delivery. + +Two options are available +Option 1. Daily AZT in antepartum period, combination of single dose of NVP at onset of labor and dose of AZT and 3TC during labor followed by combination of AZT and 3TC for 7 days in postpartum period. + +Option 2. Triple antiretroviral drugs starting as early as 14 week of gestation until one week after all exposure to breast milk has ended (AZT + 3TC + LPV or AZT + 3TC + ABC or AZT + 3TC + EFV) where ABC abacavir, LPV lopinavir. +Omission of the single dose-NVP and AZT+3TC intra­ and postpartum may be considered for women who received at least four week of AZT before delivery. If a woman received a three-drug regimen during pregnancy, a continued regimen of triple therapy is recommended for mother through the end of the breastfeeding period. + +Regimens for Infants Born to HIV Positive Mothers (a) If mother received only AZT during antenatal period: +For breastfeeding infants. Daily NVP from birth until one wk after all exposure to breast milk has ended. The dose of nevirapine is 10 mg/ day PO for infants <2.5 kg; 15 mg/ day PO for infants more than 2.5 kg. +For nonbreastfeeding infants. Daily AZT or NVP from birth until 6 wk of age. The dose of AZT is 4 mg/kg PO per dose twice a day. +If +(b) mother received triple drug ART during pregnancy and entire breastfeeding: Daily AZT or NVP from birth until 6 weeks of age irrespective of feeding + +lntrapartum lnteNentions +Avoid artificial rupture of membranes (ARMs) unless medically indicated. Delivery by elective cesarean section at 38 weeks before onset of labor and rupture of membranes should be considered. Avoid procedures increasing risk of exposure of child to maternal blood and secretions like use of scalp electrodes. + +Breastfeeding +Breastfeeding is an important modality of transmission of HIV infection in developing countries. The risk of HIV infection via breastfeeding is highest in the early months of breastfeeding. Factors that increase the likelihood of transmission include detectable levels of HIV in breast milk, the presence of mastitis and low maternal CD4+ T cell count. Exclusive breastfeeding has been reported to carry + + +a lower risk of HIV transmission than mixed feeding. Mothers known to be HIV-infected should only give commercial infant formula milk as a replacement feed when specific conditions are met (referred to earlier as affordable, feasible, acceptable, sustainable and safe (AFASS) in the 2006 WHO recommendations on HIV and infant feeding). Otherwise exclusive breastfeeding is recommended during the first 6 months of life. WHO recommends that the transition between exclusive breastfeeding and early cessation of breastfeeding should be gradual and not an "early and abrupt cessation". Replacement feeding should be given by katori spoon. + +Conclusion +HIV infection in children is a serious problem in many developing countries. The severe manifestations of HIV infection, conditions resulting from severe immuno­ supression and drug toxicities may require intensive care. Development of a vaccine to prevent HIV infection is the high priority area. There is also need to find have more efficacious antiretroviral drugs that have fewer adverse effects. Making available antiretroviral therapy at an affordable cost remains a big challenge. On short-term there is a need to find effective ways to control vertical transmission from mother to child. It may help in sub­ stantial reduction in childhood HIV infection load. + +Suggested Reading +Antiretroviral therapy of HIV infection in infants and children in resource-limited settings: towards universal access. WHO, 2006 +IAP, NACO. Guidelines for HIV Care and Treatment in Infants and Children. November 2006 +UNAIDS. UNAIDS Report on the Global AIDS Epidemic, 2012 + +Influenza +The influenza virus is capable of causing disease in humans, birds and animals. In the industrialized world morbidity, absenteeism, economic burden and mortality due to influenza is well quantified and significant. Influenza has recently gained more prominence owing to the 2009 novel HlNl pandemic. + +Etiology and Epidemiology +Influenza A and B are RNA viruses that cause human disease. Influenza A is further classified into subtypes based on the two surface proteins hemagglutinin (H) and neuraminidase (N). Influenza B is classified into two distinct lineages Yamagata and Victoria but not into subtypes. Influenza has a highly segmented genome that is prone to frequent mutations and reassortrnent. This leads to frequent antigenic "drifts" when there is minor change in antigenicity and "shifts" where there is major change in antigenicity. These phenomena of antigenic change leads to evolution of new viruses to which there is little population immunity and causes annual outbreaks and occasionally pandemics. The novel HlNl pandemic +_ e_s_s_e_n_u_a_, .P.ed_,_·a.tr.ic________________________________ +_s +_ + + +occurred due to emergence of a new swine origin influenza virus HlNl which was pathogenic to humans and capable of rapid human to human transmission and to which there was no preexisting immunity. Avian H5Nl commonly referred as bird flu is a highly pathogenic strain of influenza virus that infects and kills humans in close contact with diseased birds but has not acquired pandemic potential due to limited human to human transmissibility. The currently circulating influenza virus strains are H3N2, pandemic HlNl and influenza B. +Influenza is transmitted from person-to-person through airborne droplet spread or through contact. The portal of entry is the respiratory tract and the virus attaches itself to the respiratory epithelium through the hemagglutinin which is the main virulence factor. The incubation period is 1-3 days and the period of infectivity is usually 7 days after illness onset and sometimes longer in those with severe disease. The attack rates are highest in children and young adults. In temperate climates there is a clear defined influenza season in fall and winters but in tropical countries like India it occurs throughout the year. + +Clinical Features +In most individuals influenza is a minor illness characterized by a combination of fever, runny nose, sore throat, cough, bodyache, headache, abdominal pain, diarrhea and vomiting. The illness may have a biphasic course. Recovery usually occurs within a week. It is sometimes difficult to differentiate from common cold. Asymptomatic and subclinical infections are also very common. +A small proportion of individuals (less than 1%) can have complications and severe disease. The risk of complications is higher at extremes of age (children below 2 and the elderly), pregnant women and those who have just delivered, those with underlying comorbidities such as any chronic neurologic, metabolic, cardiac, pulmonary or renal disease, those who are immunocompromised and those with severe asthma. In the novel HlNl epidemic the elderly were spared due to pre-existent immunity and morbid obesity emerged as an important risk factor. +The most dreaded complication of influenza is pneumonia with acute respiratory distress syndrome, respiratory failure and sometimes shock and renal failure. +As many as 30% of these patients have bacterial co­ infection with S. pneumoniae and S. aureus. Progression is very rapid and most patients require ventilator support +over the next 24 hr. Occasionally other complications such as encephalitis, seizures, quadriparesis and myocarditis have been reported. Transplacental transmission to newborn and neonatal complications have also been reported. Complications usually set in by day 4 or 5 of +illness. The red flag symptoms are persistent high fever of more than 3 days duration, reappearance of fever after initial defervescence, breathlessness, dyspnea, tachypnea, hemoptysis in older children and adolescents, extreme weakness, poor oral intake and altered sensorium. + +It has been estimated that the novel HlNl pandemic caused 18,000 deaths globally with case fatality rates ranging from 0.0004% to 1.5 % (0.83% in India) and one­ third of those who died had no underlying risk factor. +Diagnosis +Influenza is primarily a clinical diagnosis. The complete blood count may show leukopenia and thrombocytopenia; the liver enzymes and CPK may be mildly elevated. Diagnosis may be confirmed by antigen detection or PCR on throat/nasopharyngeal swabs. Antibody tests in blood are not useful. Specific diagnostic tests such as PCR are not useful in routine clinical practice. They are expensive and have a turnaround time of 24-48 hr. Hence if specific therapy has to be administered, it has to be started before results become available. If the test is negative therapy cannot be discontinued as the sensitivity is only 60-70% and even lower if the sample is not properly collected. Thus the test does not help in the clinical decision of either starting or stopping therapy. In many instances, the report of the throat swab is received when the patient has already recovered. Henceforth molecular diagnosis of influenza should be restricted to hospitalized patients with severe disease when a definitive diagnosis helps in tracking the severity of the outbreak. + +Treatment +Definitive treatment of influenza is with M2 inhibitors (amantadine/ rimantidine) or neuraminidase inhibitor drugs (oseltamivir and zanamivir). These drugs reduce duration of symptoms, risk of complications and death. Though they are most effective if given within the first 48 hr of illness; therapy is useful even if given later at any time point of a severe illness. The pandemic HlNl strain and most current seasonal flu strains are resistant to the M2 inhibitors. Hence as per current recommendations oseltamivir is the first line drug and zanamivir should be used in those with oseltamivir resistant virus. The therapeutic dose of oseltamivir is 30 mg twice daily in those with weight less than 15 kg, 45 mg twice daily for 15-24 kg, 60 mg twice daily for 25-34 kg and 75 mg twice daily for those 35 kg and above. Oseltamivir though formally not approved for infants, is generally safe and may be used in a dose of 2-3 mg/kg twice daily. The duration of therapy is 5 days. In patients with very severe disease double the recommended dose for 10 days may be used. Oseltamivir is well tolerated with occasional GI and neurological side effects. +For any patient presenting with influenza like illness (ILI), the treatment strategy depends on two factors: the severity of illness and the likelihood of complications. In patients with mild disease who are not at risk for complications, only symptomatic treatment is indicated. Antibiotics and antivirals should not be prescribed. Patients should be counseled about the red flag signs and asked to seek medical care in the event these occur. These +I 239 + + +patients should be asked to stay at home till they are afebrile to prevent disease transmission to others. +Patients with ILi who are at high-risk for complications should be started on antiviral therapy irrespective of the severity of disease. The use of antivirals in all children below the age of 5 with flu like illness is however deba­ table. +For patients who present with symptoms of severe illness or who have complications, antiviral treatment with oseltamivir should be started without delay. An effort should be made to rule out other illnesses with similar symptomatology. In patients with signs of lower respiratory involvement, antibiotics like coamoxiclav or cephalosporins (cefuroxime, ceftriaxone or cefpodoxime) should also be used as bacterial coinfections are common. Supportive and intensive care is as for pneumonia or ARDS. + +Prevention +Vaccination is the most effective preventive strategy and is discussed further in Chapter 9. Chemoprophylaxis with oseltamivir is also effective in preventing influenza. The dose is 30-75 mg of oseltamivir (as per weight) to be taken once daily for 10 days. It must be remembered that chemoprophylaxis is the biggest risk factor for drug resistance. Chemoprophylaxis should be considered only for very high-risk household contacts like pregnant women and the severely immunocompromised. +Household transmission can be reduced by good ventilation in the room, proper hand hygiene and adherence to cough etiquettes. Nosocomial transmission to other patients and health care workers is a concern. Vaccination for all health care workers especially during outbreaks should be considered. All patients with suspected ILi should be isolated in single rooms or cohorted in one ward. A distance of at least 1 m should be kept between patients as the droplets can travel for this distance only. Regular disinfection of all surfaces should be carried out. The staff caring for these patients should use a well fitting surgical mask that should be changed every 4 hr. They should use hand hygiene both before and after patient contact. Negative pressure rooms, N 95 masks, gowns though ideal are possible only in high resource settings. +School children show one of the highest infection rates and outbreaks are common in school. For reducing transmission, the classrooms should be well ventilated, children should be trained in hand hygiene and cough etiquettes and sick children should be prohibited from attending school till afebrile. Temporary school closure may be considered during a pandemic. + +Suggested Reading +Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic (HlNl) 2009 Influenza. Clinical Aspects of Pandemic 2009 Influenza A (HlNl) Virus Infection. NEJM 2010;362:1708-19 + + +Emerging Viruses +This section deals briefly with some of the new emerging viral diseases seen in India. +Crimean-Congo hemorrhagic fever virus is a RNA virus of the Bunyaviridae family normally infecting cattle and occasionally transmitted to humans by infected ticks. The virus is highly contagious and human-to-human trans­ ission in household and hospital setting is not uncommon. Outbreaks have been reported from various countries including Pakistan. It was first reported from India in 2011 from Gujarat. The presentation is that ofa viral hemorrhagic fever with fever, body pain, headache, profuse bleeding, leukopenia, thrombocytopenia, altered liver functions, deranged coagulation parameters, rhabdomyolysis and renal failure. The disease mimics dengue with salient differences being early and more rapid platelet fall and rhabdomyolysis. Diagnosis is by specific PCR. Treatment is supportive; early administration of ribavarin is beneficial. Strict isolation of affected patients is crucial to prevent nosocomial transmission. +Hantaviruses cause two important clinical syndromes: hemorrhagic fever and renal syndrome (HFRS) in Europe and Asia including India and hantavirus cardiopulmonary syndrome in America. Rodents are natural hosts and humans acquire infection by inhalation of aerosols contaminated by rodent excreta or saliva. In India, HFRS and asymptomatic hantavirus infection has been reported from Tamil Nadu. The disease presents as a febrile illness with body pain, headache, thrombocytopenia, elevated liver enzymes, bleeding and renal failure. Leukocytosis with shift to left differentiates it from dengue. Diagnosis is by specific IgM antibodies. Treatment includes ribavarin and supportive care. +Nipah virus is an important cause of encephalitis increasingly reported from West Bengal, India. Its natural asymptomatic hosts are fruit bats who can transmit infection and disease to pigs and humans. Human-to­ human transmission has also been reported. Clinical features in humans are fever followed by features of encephalitis and sometimes pneumonia and respiratory distress. Mortality can be as high as 70% and there are residual sequelae in survivors. Treatment is only symptomatic. Prevention centers around limiting human exposure to raw date palm juice contaminated by fruit bat excreta and infected pigs. +Chandipura virus, a rhabdovirus, is implicated as a cause of epidemic viral encephalitis in children in several states in India but not abroad. It is transmitted by bite of infected sandflies and is associated with high mortality and neurologic sequelae. + +Suggested Reading +Chandy S, Abraham S, Sridharan G. Hantaviruses: an emerging public +health threat in India? A review. J Biosci 2008;33:495-504 +..e.s.s.e.n.t.ia•I-P••idea-.t.ri•c•--------------------------------- +s +- +- + + +Nipah virus. Wkly Epidemiol Rec 2011;86:451-5 +Patel AK, et al. First Crimean-Congo hemorrhagic fever outbreak in India. J Assoc Physicians India 2011;59:585-9 +Rao BL, et al. A arge outbreak of acute encephalitis with high fatality rate in children in Andhra Pradesh, India, in 2003, associated with Chandipura virus. Lancet 2004;364:869-74 + +COMMON BACTERIAL INFECTIONS +Staphylococcal Infections +Staphylococcus a gram-positive coccus is a very common cause of both community acquired and nosocornial disease in children. + +Etlopathogenesls +Staphylococci are functionally classified on basis of production of an enzyme and virulence factor coagulase. Coagulase positive staphylococcus is termed as S. aureus while S. saprophyticus and S. epidermidis are important coagulase negative staphylococci (CONS). CONS usually colonize the skin of all people and S. aureus the nares, axilla and perineum of around 20-25% of the population. Staphylococcal infection is acquired usually by direct contact with an infected patient or carrier and sometimes contaminated objects. Airborne spread is less common. Predisposing factors for staphylococcal infections include breach in the mucocutaneous barrier, previous viral infections such as measles, depressed immunity and prosthetic material such as shunts, central venous catheters and prosthetic joints. + +Clinical Features +S. aureus can cause a myriad of clinical infections involving almost all organs of the body. Infections are associated with suppuration and often require drainage and pro­ longed antibiotic therapy. +Commonest are infections of skin and soft tissues like furuncles, impetigo, carbuncles, abscesses and cellulitis. In some situations, the bacteria invade the fascia and muscle causing necrotizing fasciitis, an infection that is associated with very high morbidity and mortality. Staphylococcal scalded skin syndrome is another bullous infection commonly seen in infants produced by exfoliative toxin producing S. aureus that can lead to massive desquamation and denudation. + +S. aureus is an important cause of respiratory infections such as sinusitis, otitis media, pneumonia, lung abscess and empyema. Staphylococcal pneumonia commonly occurs after antecedent viral infections, is rapidly progressive and associated with a high rate of complications such as pneumatoceles, abscess and empyema. S. aureus is the commonest cause of acute infective endocarditis in both patients with native and prosthetic valves and sometimes with no risk factors. It is rapidly progressive, locally destructive and is associated with significant complications. It is also the commonest cause of + +pyopericardium an illness with high rates of constrictive pericarditis that often requires pericardiectomy. + +S. aureus is the commonest cause of musculoskeletal infections such as osteomyelitis, septic arthritis and pyomyositis. CNS infections such as meningitis usually occur following trauma or neurosurgery. S. aureus is also a common etiologic agent of subdural empyema, brain abscess and shunt infections. Enterotoxin producing S. aureus is a common cause of food poisoning that is characterized by fever and profuse vomiting. +Toxic shock syndrome (TSS) results from a locally non­ invasive toxigenic strain of S. aureus which is characterized by fever, shock, erythematous skin rash, hepatic derangement, sensorial changes and high mortality. Disseminated staphylococcal disease is another illness usually seen in previously healthy children and most commonly reported in India. It is characterized by suppurative staphylococcal infections at multiple sites either together or serially and a prolonged course. +CONS are usually pathogens of lower virulence than S. aureus. Since they colonize the skin, they are often cultured as contaminants if blood cultures are not collected by aseptic techniques. They are commonly implicated in bacteremia in low birth weight babies or in those with central venous catheters, subacute infective endocarditis, CNS shunt infections, infections associated with peritoneal dialysis catheters and prosthetic joints, urinary tract infections and postoperative surgical site infections. + +Treatment +The most important treatment strategies are surgical drainage and antibiotics. +Antibiotic therapy of staphylococcal infections has become complicated due to evolving resistance in staphylococci. More than 90% of the current day organisms are resistant to penicillin due to production of a beta lactamase/penicillinase that destroys the beta lactam ring of penicillin. Most of them however are sensitive to penicillinase resistant penicillins such as cloxacillin/methicillin and cephalosporins and are termed as MSSA. Some staphylococci however have acquired resistance to methicillin by production of an altered penicillin binding protein (PBP) and are termed as MRSA. MRSA were till some time back only reported as causative agents of hospital acquired infections but are now also being reported in community acquired infections. +The drug of choice for treating MSSA infections is cloxa­ cillin. Other alternatives are first generation cephalo­ sporins (cephalexin, cefadroxil or cefazolin), second generation cephalosporins (cefuroxime) and coamoxiclav, clindamycin. If MRSA infections are proven or suspected, drugs like vancomycin, linezolid and teicoplanin are required. +Most S. aureus infections need removal of any prosthetic material to ensure cure and prolonged therapy ranging +I Infections and Infestations � + + +from 2 weeks for bacteremia and up to 6 weeks for osteomyelitis, septic arthritis and endocarditis. + +Suggested Reading +Baranwal AK, Singhl SC, Jayashree M. A 5-yr PICU experience of disseminated staphylococcal disease, Part 1: Clinical and microbial profile. J Trop Pediatr 2007;53:245-51 +Miller LG, Kaplan SL. Staphylococcus aureus: a community pathogen. Infect Dis Clin North Am 2009;23:35-52 + +Pneumococcal Infections +Pneumococcus is one of the most common bacterial causes of pediatric infections particularly pneumonia. It is currently estimated that 50% of deaths due to severe pneumonia are caused by pneumococcus. This means that of the 400,000 deaths in children below age 5 in India due to acute respiratory infections, 200,000 are perhaps due to pneumococcus. + +Etiopathogenesis +Pneumococcus is a gram-positive diplococcus with a thick polysaccharide capsule. This capsule is the most important virulence factor and determines the various serotypes of the pneumococcus. Almost 90 serotypes of pneumococcus exist but only a handful cause disease. Serotypes 1, 4, 5, 6 A and 6B, 9V, 14, 18C, 19A, 19F and 23 are those that commonly cause human disease and are incorporated in the vaccines (Chapter 9). Pneumococci colonize the nasopharynx, colonization rates are highest in young children. Colonization can lead to infection in some individuals. Risk factors for pneumococcal disease include extremes of age (age less than two yr), splenic dysfunction, immunodeficiency especially HIV, any chronic disease and CSF leaks. + +Clinical Features +Pneumococcal infections are distributed like a pyramid, the base of the pyramid being noninvasive disease like otitis media, sinusitis and pneumonia and the apex comprising of invasive disease like bacteremic pneumonia, bacteremia and meningitis. It is estimated that for every 1000 cases of otitis media there is 1 case of meningitis. Other less common invasive diseases due to pneumococci are osteomyelitis, septic arthritis, cellulitis and peritonitis. Pneumococcus is responsible for 30% of all acute bacterial meningitis and is associated with high rate of complications like subdural empyema, morbidity and mortality. With increasing vaccination against Haemophilus influenzae, the percentage contribution of pneumococcus towards meningitis will increase further. Pneumococcal bacteremia presents as fever without focus in infants and children below age 3 and needs aggressive therapy. It is estimated that pneumococcus causes 30-50% of radiologic/ severe pneumonia. Pneumococcal pneumonia has lobar distribution with necrosis and empyema being common +complications. + +Diagnosis +The gold standard for diagnosis of pneumococcal disease is culture. However, culture yields are poor because of several reasons. Pneumococcus, unlike Salmonella, is difficult to culture especially if antibiotics have been administered. Special media containing sheep blood are required and delays in transportation and improper storage further reduce recovery. Isolation rates from blood are low and the ideal sample of lung aspirate cannot be obtained in routine clinical practice. +Other tests useful in diagnosis are Gram stain (Fig. 10.12), latex agglutination tests and PCR in CSF and pleural fluids. + +Treatment +Penicillin and its derivatives such as ampicillin and amoxicillin are the drugs of choice for treatment of pneumococcal infections. The cephalosporins particularly ceftriaxone are also satisfactory alternatives. Like many other bacteria, resistance in pneumococcus is being increasingly reported. Resistance to beta lactams is due to altered penicillin binding protein (PBP) and may be of intermediate or high level. Intermediate resistance can be overcome by using higher doses of penicillin/ amoxicillin but high level resistance requires use of alternative drugs like fluoroquinolones or vancomycin. +Prevention of pneumococcal disease is discussed in Chapter 9. + +Suggested Reading +WHO position paper. Weekly Epidemiologic record 2012;87:129-44 + +Diphtheria +Diphtheria is an acute bacterial infection caused by gram­ positive bacillus, Corynebacterium diphtheriae. + +Etiopathogenesis +The secretions and discharges from infected person or carrier are the main source of infection. The infection is transmitted by contact or via droplets of secretion. The +portal of entry is commonly the respiratory tract. The +" +• +• + + + + + + + + + + +Fig. 10.12: Gram stain of pus showing abundant gram-positive diplococci suggestive of pneumococci +_ E_s_s_e_n_t.ia•l•P••e d-ia..tric_s _________________________________ +_ +_ + + +incubation period of the disease is 2-5 days. C. diphtheriae proliferate and liberate powerful exotoxin which is the principal cause of systemic and local lesions. The exotoxin causes necrosis of the epithelial cells and liberates serous and fibrinous material which forms a grayish white pseudomembrane which bleeds on being dislodged. The surrounding tissue is inflamed and edematous. The organs principally affected by the exotoxin include the heart, kidney and myocardium. + +Clinical Features +The onset is generally acute with fever, malaise and headache. The child has a toxic look. The clinical features depend on the site of involvement. The commonest form is faucial/tonsillopharyngeal diphtheria in which there is redness and swelling over the fauces. The exudates coalesce to form a grayish white pseudomembrane, which extends to surrounding areas. The cervical lymph nodes are enlarged leading to a bull neck appearance. Sore throat, dysphagia and muffled voice are frequently present. In nasal diphtheria there is unilateral/bilateral sero­ sanguinous discharge from the nose and excoriation of upper lip. In laryngotracheal diphtheria, the membrane over the larynx leads to brassy cough, stridor and respiratory distress. Diphtheritic lesions may occasionally also be found in skin and conjunctiva. +The commonest complication is respiratory failure due to occlusion of the airways by the membrane. Myocarditis generally occurs by second week of illness and can lead to symptoms of congestive cardiac failure, arrhythmias and sudden death. +Neurological complications include: (i) palatal palsy, which occurs in second week and is clinically manifested by nasal twang and nasal regurgitation; (ii) ocular palsy in third week; (iii) loss of accommodation, manifested by visual blurring and inability to read; and (iv) generalized polyneuritis occurs by 3rd to 6th weeks of illness. Renal complications include oliguria and proteinuria. + +Diagnosis +There should be a high index of suspicion. Rapid diagnosis is enabled by Albert stain of a swab from the oropharynx and larynx. Culture, however, takes eight hr to become available. Faucial diphtheria should be differentiated from acute streptococcal membranous tonsillitis (patients have high fever but are less toxic and the membrane is confined to the tonsils), viral (adenovirus) membranous tonsillitis (high fever, sore throat, membranous tonsillitis with normal leukocyte count, self limited course of 4-8 days), herpetic tonsillitis or aphthous stomatitis, thrush, infectious mononucleosis, agranulocytosis and leukemia. + +Management +The most important component of therapy is neutralization of bacterial toxin by administration of antitoxin. Diphtheria antitoxin (IV/IM) should be administered soon + + +as infection with diphtheria bacilli is suspected even earlier than bacteriological confirmation before the bacteria have fixed to the tissues. The degree of protection offered by the diphtheria antitoxin is inversely proportional to the duration of clinical illness. Repeat doses of antitoxin may be given if clinical improvement is suboptimal. +Antibiotics such as penicillin or erythromycin should be used to terminate toxin production, limit proliferation of bacteria, to prevent spread of organism to contacts and to prevent the development of carriers. This should be followed by active immunization as clinical disease does not confer active immunity. +Bed rest is advocated for two to three weeks. Children should be monitored for airway obstruction and managed; tracheostomy may be required in some cases. Sudden exertion should be avoided and changes in rate and rhythm of heart should be looked for. Children with palatal palsy should be fed by nasogastric feeding. Generalized weakness due to polyneuritis is treated as for poliomyelitis or Guillain-Barre syndrome. + +Prevention and Control +The patient should be isolated until two successive cultures of throat and nose are negative for diphtheria bacillus. All contaminated articles from discharges should be disinfected. All household and other contacts should be observed carefully for development of active lesions, cultured for C. diphtheria and given chemoprophylaxis with oral erythromycin for 7 days or single dose benzathine penicillin. Previously immunized asymptomatic patients should receive a booster dose of diphtheria toxoid. Those not fully immunized should receive immunization for their age (see Chapter 9). + +Suggested Reading +Panchereon C. Clinical features of diphtheria in Thai children: a historic perspective. South-east Asian J Trop Med Public Health 2002; 33:352-4 +Zakikhany K, Efstratiou A. Diphtheria in Europe: Current problems and new challenges. Future Microbiol 2012;7:(5)595-607 + +Pertussis (Whooping Cough) +Pertussis is an acute highly contagious respiratory tract infection, caused by Bordetella pertussis. It may affect any susceptible host but is more common and serious in infancy and early childhood. The disease is characterized by intense spasmodic cough. Similar illness is also caused by B. parapertussis, B. bronchoseptica and adenoviral infections 1, 2, 3 and 5. The worldwide prevalence of the illness has declined following widespread vaccination. + +Epidemiology +Pertussis is extremely contagious with attack rates as high as 100% in susceptible individuals exposed to aerosol droplets. B. pertussis does not survive for prolonged periods in the environment. Chronic carriage in humans is not known. After intense exposure as in households, +Infections and Infestations - + + + +the rate of subclinical infection is as high as 80% in fully immunized and naturally immune individuals. Protection against typical disease wanes 3-5 yr after vaccination and is unmeasurable after 12 yr. Coughing adolescents and adults are the major reservoir of B. pertussis and are the usual sources for index cases in infants and children. + +Features +The incubation period of the disease is 7-14 days. The clinical presentation can be divided into three stages. +The catarrhal phase lasts for 1-2 weeks and is the most infectious period. The initial manifestations are indistin­ guishable from upper respiratory tract infections. The child has cough, coryza with little nasopharyngeal secretions. Unlike the upper respiratory infections, the cough does not improve in a few days but becomes more severe and frequent with the passage of time. Though the cough may not be typically paroxysmal in early stages, it tends to be annoying and frequent at night. The paroxysmal nature of the cough is suspected towards the latter part of this phase. +The paroxysmal stage lasts for 2-6 weeks in which cough progresses to episodic paroxysms of increasing intensity ending with high-pitched inspiratory whoop. The whoop is produced by the air rushing in during inspiration through the half-open glottis. The whoop may not always be present in infants who present with apneic or cyanotic spells. The child coughs up thick tenacious mucus. The paroxysms of cough may occur frequently and terminate by vomiting. Repeated thrusting of tongue over the teeth causes ulceration of the frenulum of the tongue. Paroxysms of cough are precipitated by food, cold air and cold liquids. In infants <3 months, this stage may be considerably prolonged. +In the convalescent phase the intensity and paroxysms of cough decrease gradually over 1-4 weeks. The vomiting becomes less frequent. Appetite, general condition and health gradually improve. +Complications +Respiratory complications include otitis media, pneumonia, atelectasis, emphysema, bronchiectasis, pneumothorax and pneumomediastinum +• Neurological complications include seizures and encephalopathy (2-7%). +• Bleeding episodes, e.g. epistaxis, retinal or sub­ conjunctival bleeds, intracranial hemorrhage. +• Inguinal hernia, rectal prolapse. +• Malnutrition due to persistent vomiting and disincli­ nation to eat because of fear of paroxysms of cough with attempts at feeding. +• Flare up of tuberculosis. + +Diagnosis +The diagnosis of whooping cough is based on clinical features. There may be a lymphocytic leukocytosis and + +low ESR. Specific diagnosis depends on isolation of the organism from nasopharyngeal swab or cough plate cultured on Bordet-Gengou medium, which is often positive in the catarrhal and paroxysmal stage. Other conditions that present with prolonged episodes of spasmodic cough include adenoviral infection, endo­ bronchial tuberculosis, inhaled foreign body and reactive airway disease. + +Management +General measures include providing adequate nutrition and hydration and avoiding factors aggravating cough. The antibiotic of choice is erythromycin (40-50 mg/kg/ day in 3 divided doses) given for 14 days. It terminates the respiratory tract carriage of B. pertussis thus reducing the period of communicability but does not shorten the course of illness. Nebulization with salbutamol is effective in reducing bronchospasm and controlling bouts of cough. If nebulization is not possible, salbutamol may be given orally. Cough suppressants and antihistaminic agents should be avoided. + +Prevention +Chemoprophylaxis with erythromycin is recommended for close family contacts especially children <2-yr-old. Children under 7 yr of age should be vaccinated (Chapter 9). + +suggested Reading +Wood N, McIntyre P. Pertussis: Review of epidemiology, diagnosis, management and prevention. Paediatric Respiratory Reviews 2008;9:201-12 +Zouari A, Srnaoui H, Kechrid A. The diagnosis of pertussis: which method to choose? Crit Rev Microbiol 2012;38(2):112-21 + +Enteric Fever +The term enteric fever includes typhoid fever caused by Salmonella enterica var typhi and paratyphoid fever caused by S. enterica var paratyphi A, B or C. Paratyphoid infections constitute about 20% of all cases of enteric fever worldwide. As enteric fever is a disease transmitted by the feco-oral route, its greatest burden is in resource­ limited countries where water supply and sanitary conditions are poor. In a community-based study in urban slums of Delhi the incidence was estimated to be 980/ 100,000 population. Enteric fever is the most common cause of fever lasting for more than 7 days in clinical practice in India. + +Etiopathogenesis +S. enterica serotype typhi/paratyphi is a gram-negative, non­ lactose fermenting, flagellate bacterium. The somatic or 0 antigen is shared among various salmonellae; the flagellar or H antigen is specific to the serovar. S. enterica var typhi also possesses a Vi polysaccharide capsule. +The infective dose of typhoid/paratyphoid bacillus varies from 103 to 106 organisms. The organism must +_ E_s_s_e_n_t .ia•l•P•e•d·i-at.r.ic_________________________________ +_s +_ + + +survive the gastric barrier to reach the small intestine; hence, conditions which reduce gastric acidity, such as use of antacids, H2 receptor blockers and proton pump inhibitors, reduce the infective dose. On reaching the small intestine, the organism penetrates the mucosa and infects the lymphoid follicles and subsequently the draining mesenteric lymph nodes and the liver and spleen. It multiplies in the reticuloendothelial system and after incubation period varying from 7 to 14 days spills into the bloodstream and is widely disseminated, especially to liver, spleen, bone marrow, gallbladder and the Peyers patches of the terminal ileum. This spill marks the onset of clinical manifestations of enteric fever. Infection leads to both local and systemic immune responses, which are, however, inadequate to prevent relapse or reinfection. + +Clinical Features +There is no appreciable difference between the manifestations of typhoid and paratyphoid fever. The hallmark of enteric fever is fever which starts as a low grade fever and then shows stepwise increase peaking to as high as 103-104 °C by the end of the first week. This pattern differentiates it from viral fever where the peak is usually at the onset of fever. With fever, there is associated malaise, dull headache, anorexia, nausea, poorly localized abdominal discomfort, mild cough and malaise. There may be diarrhea; constipation in children is rare. Physical findings are unremarkable with the exception of a coated tongue, tumid abdomen and sometimes hepatosplenomegaly. The rash described in Western textbooks is seldom or never seen in Indian subjects. Infants and young children with enteric fever may have diarrhea as a predominant manifestation or a short-lasting undifferentiated febrile illness. In the absence of treatment fever may continue for 3-4 weeks followed by natural remission or by development of complications. + +Complications +The commonest intestinal complications are bleeding or perforation seen in the 2nd or 3rd week of illness in 10-15% adult patients, but less frequently in children. Bleeding is due to erosion of a necrotic Peyers patch through the wall of a vessel and is usually mild but can, sometimes, be life-threatening. Perforation is a dreaded complication manifesting as acute abdomen, with high mortality unless appropriately treated. +The term severe or complicated enteric fever is used for patients presenting with neurological complications such as delirium, coma, obtundation, stupor and/ or shock and is associated with mortality rates as high as 50%. Other complications of enteric fever include splenic abscesses, hepatitis, cholecystitis, pneumonia, disseminated intra­ vascular coagulation and other manifestations such as psychosis, ataxia or meningitis. The case fatality rate is less than 1% in appropriately treated cases but may be 10- 20% in inadequately treated or complicated cases. + + +Relapse Relapse may occur in 5-15% of treated cases, usually due to the organism with the same susceptibility as the original attack and is relatively a milder illness. Rate of relapse is dependent on choice of drug therapy. It is higher with beta lactams such as cefixime or ceftriaxone as compared to quinolones and azithromycin. +Carrier state Although 5-10% adult patients may shed salmonella in stool following an acute attack for up to 3 months, only 1-4% excrete bacilli for more than 1 yr. These individuals are potential sources of infection for family members and contacts and for the community if they are in occupations that involve food-processing. There is no data on carrier prevalence in children and routine culture of stool following recovery from enteric fever is not recommended. + +Diagnosis +Leukocyte counts may be normal to low with absolute eosinopenia and neutrophilic predominance. Anemia and thrombocytopenia may occur in advanced illness. There may be mild elevation of transaminases to 2-3 times normal (SGOT higher than SGPT). A high C reactive protein (CRP) helps to differentiate enteric from viral fevers especially dengue. +The gold standard for diagnosis is blood culture. The sensitivity is greatest in the first week at around 90% but drops to 40% in the 4th week. Salmonella is an easy organism to culture and use of bile broth media and automated culture systems such as BACTEC improve recovery. Sufficient blood should be collected (10 ml in adults and 5 ml in children) and a blood: media ratio of 1:5 should be maintained. Bone marrow cultures have higher yield as compared to peripheral blood cultures as Salmonella is a pathogen of the reticuloendothelial system and should be done when patients present in later stages of the illness. Stool and urine cultures are not recom­ mended. Antimicrobial susceptibility testing of the isolate is important. +The Widal test detects presence of IgG and IgM anti­ bodies to H(flagellar antigen) of S. enterica var typhi and paratyphi A and B, and O (somatic antigen) common to typhi and paratyphi A and B. Anti O titers are both IgG and IgM that rise and decline early, while anti H are primarily IgG that rise and decline late in course of the disease. The conventional method of interpretation of the Widal test has been to demonstrate four-fold rise in antibody titers in two samples. A single titer of at least 1:160 for both O and His also considered positive. The sensitivity of the test is low in the first week of illness and in patients treated with prior antibiotics. Specificity is low owing to anamnestic reactions, prior vaccination, cross reactivity with other Enterobacteriaceae and subclinical infections in endemic areas. Other tests such as Tubex and Typhidot that detect IgM antibodies against typhoid have not proven superior to the Widal test. +Infections and Infestations - + + + +Treatment +Indications for inpatient treatment Most cases of enteric fever can be managed at home with oral antibiotics and advice to seek medical followup in case of failure to respond to therapy or development of complications. Children with persistent vomiting, inability to take orally, severe diarrhea or abdominal distension usually require intravenous antibiotics therapy and intravenous fluids, necessitating admission to hospital. + +Antimicrobial susceptibility Though resistance to chloramphenicol was first noted soon after its first use in the 1940s, it was not until 1972 that chloramphenicol­ resistant typhoid fever became a major problem. Multi drug resistant typhoid fever (MDRTF) became a common occurrence by the end of 1990s, with emergence of S. typhi simultaneously resistant to all the drugs that were used as first-line treatment (chloramphenicol, trimethoprim, sulfamethoxazole and ampicillin). Fluoroquinolones, introduced in the late 1980s and early 1990s, produced very good results initially, but the past decade has seen a progressive increase in the minimum inhibitory concen­ trations of ciprofloxacin in S. typhi and paratyphi. Since minimum inhibitory concentrations are below the stan­ dard susceptibility breakpoint, laboratories report bacteria as sensitive to fluoroquinolones; but the use of fluoro­ quinolones is associated with a high incidence of clinical failure because drug levels needed to kill organisms are not achieved with standard doses, and often, even with highest tolerated doses. Now that the susceptibility breakpoints have been revised downwards, this discor­ dance between in vitro and in vivo susceptibility will be resort. Resistance to nalidixic acid has been suggested as a marker of fluoroquinolone failure. +Currently, third-generation cephalosporins such as ceftriaxone and cefixime are the first-line agents for therapy of enteric fever. Azithromycin is a new drug that is being used as an alternative agent. + +Choice for empirical therapy For uncomplicated ente­ ric fever, oral cefixime at a dose of 20 mg/kg/day is the drug of choice, both for sensitive and multidrug resistant S. typhi. In areas where quinolone resistance is infrequent (rare at the moment in India), fluoroquinolones may still be considered the drugs of choice; however, if both quinolone resistance and resistance to other drugs (like amoxicillin, chloramphenicol, cotrimoxazole) are wide­ spread, the only options are oral cefixime or azithromycin. +Azithromycin (10-20 mg/kg/ day) is a good second choice agent; chloramphenicol (50 mg/kg/day), amoxicillin and cotrimoxazole are other second-line agents. The choice of medication depends on individual preference, experience and level of comfort and cost considerations. Once culture results are available, therapy can be modified. There is no data at present to support use of combination therapy in enteric fever. + + +For severe illness and where complications are present, intravenous ceftriaxone and cefotaxime are used at a dose of 100 mg/kg/day. In patients with history of penicillin or cephalosporin allergy, aztreonam, chloramphenicol (in higher than usual doses) or cotrimoxazole (in higher than usual doses) are used as second-line agents. Parenteral treatment is continued until defervescence has occurred, oral intake has improved and complications resolved. Thereafter, therapy can be switched to oral cefixime to complete a total duration of 14 days. Other oral drugs that may be used for switch over therapy include cefpodoxime, azithromycin, cotrimoxazole and amoxicillin. However, the experience with cefpodoxime is limited and the other agents require switch to a different class of antimicrobials than cephalosporins. +If cultures are positive and show quinolone sensitivity, therapy should be changed to ciprofloxacin at a dose of 20 mg/kg/day as quinolones are associated with faster defervescence and lower relapse rates as compared to ceftriaxone. If cultures are positive and show quinolone resistance as well as sensitivity to other drugs ampicillin, chloramphenicol and cotrimoxazole), it is prudent to continue with ceftriaxone alone rather than change because the older drugs do not offer any advantage over ceftriaxone. If cultures are negative and defervescence has not occurred by day 7, a thorough search for alternative etiology for fever should be made and ceftriaxone continued. There is no role for changing the antimicrobial agent or adding another drug, since ceftriaxone resistance is still anecdotal. + +Therapy of relapses Relapse rates vary with the type of drug and are most common with beta lactams (ceftriaxone, cefixime) especially if shorter duration of therapy is used. Usually relapses may be satisfactorily treated with the same drug as used for primary therapy but at appropriate dose and duration. However, if the isolate is quinolone sensitive and fluoroquinolones were not used for primary therapy, they should be used for treatment of the relapse. + +Therapy of carriers The carrier state is uncommon in children and testing for chronic carriage 3 months after an episode of enteric fever is not recommended. However, if chronic carriage is demonstrated, treatment with amoxicillin (100 mg/kg/day) with probenecid (30 mg/ kg/day) or cotrimoxazole (10 mg/kg/day) for 6-12 weeks is recommended. If the strain is nalidixic acid sensitive, quinolones for 28 days is a better option. + +Prevention +The most effective and desirable method for preventing enteric fever is by improving hygiene and sanitation. This will yield additional dividends of reduction in the burden of other water-borne illnesses as well. Vaccination is a major preventive strategy. +___ _s_s_e_n_t.ai_i_Pe _d.ia.t.ri_c _________________________________ _ +_s +E +_ + + +Suggested Reading +Kundu R, Ganguly N, Ghosh TK, Yewale VN, Shah RC, Shah NK; IAP Task Force. Report: diagnosis of enteric fever in children. Indian Pediatr 2006;43:875-83 +Kundu R, Ganguly N, Ghosh TK, Yewale VN, Shah RC, Shah NK; lAP Task Force. Report: management of enteric fever in children. Indian Pediatr 2006;43:884-7 +Parry CM, Hien TT, Dougan G, White NJ, Farrar JJ. Typhoid fever. N Eng J Med 2002;347:1770-82 + +Leptospirosis +Leptospirosis is a zoonotic disease of worldwide distri­ bution, caused by spirochetes. Most cases occur in tropical and subtropical countries. While rats are the principal source of human infection, dogs, cats, livestock and wild animals are other reservoirs. Infected animals may excrete spirochete in urine for several weeks. The survival of excreted organisms depends on the moisture content and temperature of the soil. Humans acquire infection after getting exposure to water or soil contaminated with rat urine. Agricultural workers, veterinarians, meat handlers, rodent control workers and laboratory personnel are at risk of getting infected because of occupational exposure. Infection is common in the monsoons and during flooding. + +Pathogenesis +Leptospira enter the body through abrasions and cuts in skin or through mucous membranes and spread to all organs hematogenously. The organisms damage the endothelial lining of small blood vessels, with leakage and extravasation of blood cells, hemorrhage and ischemic damage to various organs including liver, kidneys, meninges and muscles. + +Clinical Features +Human infection ranges from asymptomatic infection to a severe multiorgan involvement which is often fatal. Symptomatic infection is a relatively mild as an anicteric febrile illness in over 70% of patients; about 20% present as aseptic meningitis, while severe leptospirosis with hepatorenal dysfunction (Weil disease) develops in 5-10% of individuals. The incubation period is usually 1-2 weeks. The illness is often biphasic. In the initial or septicemic phase lasting 2-7 days, the onset is abrupt with high grade fever with rigors and chills, lethargy, severe myalgia, headache, nausea, vomiting. There may be conjunctiva! suffusion with photophobia and orbital pain, generalized lymphadenopathy and hepatosplenomegaly. Transient maculopapular rash may be seen in <10% cases. Hypo­ tension with bradycardia and circulatory collapse is rare. Some patients develop acute respiratory distress syndrome with respiratory failure. Most patients are +asymptomatic within one week. +In some patients, after a brief asymptomatic phase, the second phase, called the immune or leptospiruric phase, +becomes manifest where Leptospira localize to tissues to +cause specific signs and symptoms. In this phase, + +circulating autoantibodies to Leptospira are present; organisms can no more be isolated from blood or CSF but persist in tissues like kidneys and aqueous humor. During the immune phase, some children develop aseptic meningitis or uveitis with recurrence of fever. Encephalitis, cranial nerve palsies, paralysis and papilledema are rare. Central nervous system abnormalities usually normalize within 1 week; mortality is rare. +In icteric Ieptospirosis (Weil syndrome) after the initial +phase of fever patients develop severe hepatic and renal dysfunction. Jaundice and hepatomegaly are usually detected; splenomegaly is found in 20%. Renal failure may develop, often during the second week of illness. All patients have abnormal urinary finding on urinalysis in the form of hematuria, proteinuria and casts. Azotemia is common, often associated with oliguria or anuria. Hemorrhagic manifestations are rare but when present, may include epistaxis, hemoptysis and gastrointestinal and adrenal hemorrhage. Transient thrombocytopenia may occur, and mortality is 5-15%. +Diagnosis +Complete blood count shows anemia, leukocytosis with polymorph predominance and thrombocytopenia. The CRP is elevated and liver enzymes are mildly elevated with SGOT more than SGPT. The CPK is high. In patients with Weil disease there is elevated serum creatinine, deranged coagulation parameters and direct hyper­ bilirubinemia with raised transaminases. +Specific diagnosis is established by serologic testing, microscopic demonstration of the organism or culture. The gold standard for serologic diagnosis is the microscopic agglutination test (MAT), which is only available in reference centers. Commercial kits for serologic diagnosis include rapid tests and IgM ELISA. These tests are positive after 5 days of illness. Cross reactivity and false positivity is seen with other infections like enteric fever and malaria. Demonstration of organism in tissues or urine by dark field microscopy or immunoflorescence and cultures are not routinely available. +Leptospirosis should be differentiated from other febrile illnesses commonly seen in the monsoon season like malaria, dengue, enteric fever, acute viral hepatitis and hantavirus infections. +Treatment +Treatment should be initiated as early as possible. For a severe case of leptospirosis, parenteral penicillin G (6-8 million U /m2 /24 hr q 4 hr IV) for 7 days is the drug of choice. Ceftriaxone and IV tetracycline are also acceptable alternatives. For oral treatment amoxicillin and doxycycine (in children above 8 yr) are the drugs of choice. +Prevention +Prevention entails avoidance of exposure to contaminated water. Single dose doxycyline or amoxicillin following +Infections and Infestations - + + + +exposure can prevent illness but is not routinely recommended. + +Suggested Reading +Tullu MS, Karande S. Leptospirosis in children: a review for family +physicians. Indian J Med Sci 2009;63:368--78 + +Tetanus +Tetanus is caused by the bacterium Clostridium tetani, a spore forming, anerobic, gram-positive motile bacillus, found in human and animal feces. Its spores are widespread in the environment. Tetanus commonly occurs in areas where soil is cultivated, in rural areas, in warm climates and during summer months. According to WHO estimates, it contributes to 8% of vaccine preventable deaths. + +Pathogenesis +C. tetani is a noninvasive organism. The spores of the organism remain nonpathogenic in soil or contaminated tissues until conditions are favorable for transformation into vegetative form. Transformation occurs in the presence of locally decreased oxygen reduction potential, typically in devitalized tissue, in the presence of a foreign body, trauma and crush injury and suppurative infections. Two types of toxins are produced by the organism, tetanolysin and tetanospasmin. Tetanospasmin, is the main toxin responsible for the manifestations of the disease. It binds to the neuromuscular junction at the site of injury, and undergoes retrograde axonal transport to reach the presynaptic nerve terminal where it prevents the release of inhibitory neurotransmitters glycine and GABA leading to uncontrolled contraction of muscles. + +Clinical Features +Tetanus mainly affects the unimmunized and partly immunized individuals. The disease may occur in various forms: neonatal, generalized, localized and cephalic. The most common forms are generalized and neonatal tetanus. + +Generalized tetanus has an incubation period of approxi­ mately 8 days (range 2-14 days). However, the disease may occur months after the initial injury. The incubation period depends on the distance of the site of injury from the central nervous system. The faster is the onset of symptoms, the poorer is the prognosis. Characteristically, there is descending paralysis, with initial involvement of the jaw muscles. There is spasm of the masseters leading to trismus or lockjaw. Subsequent involvement of the neck, back and abdominal muscles occurs, soon involving the whole body. As the disease progresses, minimal stimuli may lead to generalized spasms, which are the hallmark of the disease and contribute to serious complications and death. Typically, the sensorium of the patient is preserved. There is difficulty in swallowing. Autonomic instability + +may occur, with blood pressure fluctuations in the form of hypertension or hypotension, diaphoresis and arrhythmias. Recovery usually begins after 3 weeks and approximately takes four weeks. Recovery from tetanus occurs by sprouting new nerve terminals in the spinal cord leading to relaxation of the contracted muscles. + +Neonatal tetanus is a major cause of mortality in developing countries. Pregnant women who are not immunized against tetanus do not pass on protective antibodies to their babies. Infection results of unhygienic birth practices, most commonly when the umbilical cord is contaminated at the time of cutting after delivery. Symptoms usually appear by the third day afterbirth, never in the first two days of life and rarely after the age of two weeks. Excessive unexplained crying followed by refusal of feeds and apathy are the common initial symptoms. The baby develops progressive feeding difficulty, becomes rigid, develops paralysis and may develop opisthotonic posturing and experience painful spasms. The mouth is kept slightly open due to pull and spasm of the neck (Fig. 10.13). Reflex spasm of the masseter makes feeding painful. Pharyngeal muscles go into spasm and cause dysphagia and choking, lockjaw or reflex trismus followed by spasms of limbs. There is generalized rigidity and opisthotonus in extension. Spasm of larynx and respiratory muscles are characteristically induced by stimuli such as touch, noise and bright light, resulting in episodes of apnea and cyanosis. Constipation persists until the spasms are relieved. In.tercurrent infections, dehydration and acidosis may complicate the clinical picture. It has a very high case fatality rate of 70 to 100%. + +Localized tetanus is less severe in comparison and is characterized by rigidity and pain confined to the muscles adjacent to the wound. It may lead to generalized tetanus later. In patients with isolated localized tetanus, the mortality is less than 1 %. Cephalic tetanus is a form of local tetanus, which occurs due to injury of the bulbar muscles. It has a poor prognosis. + + + + + + + + + + + + + + + +Fig. 10.13: Neonatal tetanus. Courtesy: Dr Amarjeet Mehta, Jaipur +--E•s•s•e•n•t• a•l•P•e•d• i•a ·.tcn. -------------------------------- +i +s +·. +- + + +Treatment +Most patients require intensive care management and good supportive care. The aims of treatment are airway maintenance, prevention of further toxin absorption, relieving clinical features, e.g. spasms, controlling autonomic instability and antibiotics. Airway manage­ ment may require intubation and mechanical ventilation, especially in severe cases and if the infant gets frequent episodes of largyngeal spasms, apneic attacks with cyanosis or central respiratory failure. Neutralization of free toxin is done by administering human tetanus immunoglobulin (TIG); however, antitoxin cannot dislodge the toxin already fixed to the nerve roots. The route of administration is intramuscular or intrathecal. The usual dose is 500 to 1000 IU. Antibiotic therapy is needed to abolish the bacteria from the wound site. The commonly used antibiotics are crystalline penicillin or metronidazole. +Spasms are precipitated by minimal stimuli, therefore, efforts should be made to avoid noxious stimuli including bright lights, pain and loud noises. Patient should be kept in a dark, quiet and isolated room, which should be lighted well to permit observation of the child; handling should be minimum. Intramuscular injections must be avoided. Temperature should be maintained within normal limits. Relief of spasms is done by using benzodiazepines. The most commonly used agent is diazepam, either as an intermittent IV bolus or as continuous infusion. Diazepam prevents further spasms by causing GABA-mediated central inhibition. It also helps by reducing anxiety and promoting muscle relaxation. Other agents used for severe spasms include pancuronium bromide. +Supportive care includes adequate hydration, early detection of myoglobinuria and prevention of renal shutdown. Oropharyngeal secretions should be sucked periodically. Maintenance of oxygen is important. Oral feeding should be stopped and an IV line should be established for providing adequate fluids, calories and electrolytes and for administration of medications. After three to four days of treatment, milk feeding through nasogastric tube may be started. Autonomic instability is controlled with the use of alpha and beta adrenergic blockers, like propranolol and labetalol. Intravenous magnesium is effective in decreasing autonomic instability and treating muscle spasms. +All patients should receive a complete course of immunization with tetanus toxoid once recovered, as the disease does not induce protective antibodies. + +Prognosis +The disease has high mortality rate in spite of adequate supportive care, which may reach up to 50% in severe generalized tetanus and 90% in neonatal form. The outcome depends on the incubation period, the site of injury, the rate of progression of illness and presence of + + +autonomic instability. Survivors do not manifest any neurological sequelae, except when apneic episodes are unduly prolonged and unattended. The prognosis in neonatal tetanus is worse if the (i) onset of symptoms occurs within the first weeks of life, (ii) interval between lockjaw and onset of spasms is less than 48 hr, (iii) high fever and tachycardia are present, and (iv) spasms, especially of larynx resulting in apnea are severe and frequent. + +Prevention +Immunization with tetanus toxoid leads to induction of protective antibodies (Chapter 9). Maternal and neonatal tetanus can be effectively prevented by immunizing the mother during pregnancy, and ensuring clean delivery and cord care. + +Suggested Reading +Okoromah CN, Lesi FE. Diazepam for treating tetanus. Cochrane Database Syst Rev 2004; CD003954 +Roper MH, Vandelaer JH, Gasse FL. Maternal and neonatal tetanus. Lancet 2007;370:1947-59 +Singhi S, Jain V, Subramanian C. Post-neonatal tetanus: issues in intensive care management. Indian J Pediatr 2001; 68:267-72 + +Rickettsial Infections +Rickettsial diseases are a group of febrile illnesses caused by obligate intracellular gram-negative bacilli and transmitted to man by arthropod vectors. + +Etiopathogenesis and Epidemiology +Rickettsia are a group of motile, gram-negative, nonspore forming highly pleomorphic bacteria that present as cocci, rods or thread like obligate, intracellular parasites. Scrub typhus caused by R.tsutsugamushi, Indian spotted fever caused by R.conorii and Q fever caused by C. burnetti are the rickettsial infections prevalent in India. Cases have been reported from all states chiefly from rural and forested areas and occasionally also from urban areas. +Scrub typhus is transmitted by bite of the trombiculid mite and Indian spotted fever by ticks. Rickettsial disease is due to invasion of the endothelial region of the vas­ culature and subsequent microvasculitis. This process especially affects the brain, cardiac and skeletal muscle, skin, liver, lungs and kidneys. + +Clinical Manifestations \ No newline at end of file