diff --git "a/notes/Ghai-Essential-Pediatrics_5.txt" "b/notes/Ghai-Essential-Pediatrics_5.txt" new file mode 100644--- /dev/null +++ "b/notes/Ghai-Essential-Pediatrics_5.txt" @@ -0,0 +1,2141 @@ + + +• Early onset hypocalcemia: Presenting within 3 days of life and is usually asymptomatic, detected on investi­ gation. It is especially seen in premature babies, infants of diabetic mothers and those with birth asphyxia. +• Late onset hypocalcemia presents as classical neonatal tetany, jitteriness and seizures. Feeds with higher phosphate load such as cow milk and some formulae, result in hyperphosphatemia with subsequent hypo­ calcemia. +Management +This has been discussed in appropriate sections. +Jaundice Problems +• Larger RBC volume for body weight +• Immaturity of hepatic enzymes and hepatic excretory capacity +• Immature blood brain barrier-increased risk for bilirubin encephalopathy +Management +This has been discussed in section on jaundice. + +Hematological Abnormality +Problems +Polycythemia. Placental insufficiency with intrauterine hypoxia leads to stimulation of erythropoiesis and resul­ tant polycythemia, especially seen in IUGR babies. Poly­ cythemia (>65% hematocrit) produces hyperviscosity with decreased organ perfusion. Manifestations include jitteri­ ness, respiratory distress, cardiac failure, feeding intolerance, hypoglycemia, hypocalcemia and hyperbilirubinemia. +Anemia. Accelarated destruction of fetal RBCs, low reti­ culocyte count and inadequate response of the bone marrow to erythropoietin cause anemia of premaurity. Low iron stores, higher incidence of sepsis and frequent blood sampling in LBW babies further predisposes to risk of severe anemia. +Management +• Treatment of polycythemia: Symptomatic infants or those with hematocrit >75% require partial exchange trans­ fusion. For others, management includes increasing the fluid intake. +• Anemia: +- Iron supplementation: All LBW babies should be started of 2-3 mg/kg of iron from 2 months till 2 yr of age. +- Sampling should be mized and in small amounts - Transfusions may be given as per institution protocol. +Immature Organ Systems in Preterms +Respiratory distress syndrome. This has been described in detail later. +Intraventricular hemorrhage. Preterms have a fragile highly vascular collection of vessels near the lateral ventricle of + + +brain. Respiratory distress, mechanical ventilation or vigorous resuscitation, can cause rupture of these vessels leading to adverse neurological sequelae. Preventive measures include minimal and gentle handling, avoiding rapid changes in intravascular volume such as rapid boluses or infusion of hyperosmolar solutions, avoiding high pressures during ventilation and treating any bleeding diathesis. Treatment is essentially supportive and management of later complications such as hydrocephalus. +Retinopathy of prematurity (ROP). Growth of retinal vessels occurs from the optic disc to the periphery from 18 weeks of gestation till term. Any injury to these vessels due to the still developing vessels of preterm retina when subjected to the premature transition of postnatal life (especially high oxygen saturation as may be used during resuscitation), may pathological proliferation, resulting in retinal damage with vision loss, if left untreated. This complication can be +decreased with rational use of oxygen, maintaining a Sp02 +between 85-95% and regular screening for early detection and treatment. Advanced stages of ROP requires peripheral retinal ablation by laser or cryotherapy. +Hearing damage. Preterm infants are at higher risk of hearing loss due to immaturity and complications thereof such as infections or drugs. Adjustment of drug doses according to gestational age, preventing hypoxia, treating jaundice and routine screening for early detection can minimize this complication. + +Associated Conditions +An IUGR birth itself might be an indication of a pre­ existing problem leading to such occurrence. Examples include intrauterine infections and chromosomal anomalies which result in IUGR. These usually constitute a sub oup of IUGR babies known as symmetrical IUGR. The cause of growth restriction is a condition other than nutritional deficiency and onset occurs early in fetal life with propor­ tionate restriction of head and body, unlike the nutri­ tionally restricted asymmetrical IUGR which has onset in third trimester and has head growth is spared. +gr + +Prolonged Hospital Stay +Requirement of frequent monitoring and intervention in these high risk babies results in their separation from parents at birth, and high cost. It is an emotionally and financially trying time for all families. Keeping parents involved in decision making with counseling sessions directed at their concerns helps greatly in management. + +Criteria for Discharge +• Screening tests are performed before discharge or on followup, e.g. those for ROP detection in infants <32 weeks and auditory brainstem evoked response (ABER). +• Nutrition supplements including multivitamins, iron, calcium and vitamin D are started. +- Essential Pediatrics + + + +• Immunization with BCG, Hep B and OPV is given. +• Weight gain should be consistently demonstrated for few days before discharge. Weight, length and head circumference should be recorded at discharge and plotted on a growth chart, which can be used on follow­ up to determine if growth is adequate. +• Baby should be feeding well; if on alternate feeding technique like paladai feeding, the mother should be confident regarding its details. +• Absence of danger signs and completion of treatment like IV antibiotics. If baby is being discharged on oral medication then parents should be well educated regarding how to administer. +• Methods of temperature regulation, either KMC practice or other methods should be well known to parents. +• All danger signs are explained in detail to parents with information regarding whom and where to contact clearly highlighted. +The following are the danger signs: - History of difficulty in feeding +- Movement only when stimulated +- Temperature below 35·5°C or 37·5°C or more - Respiratory rate over 60 breaths per minute - Severe chest indrawing +- History of convulsions +• Followup within 3-7 days of discharge to ensure the baby has been adapted well to home environment. + +Feeding of LBW Babies +Nutritional management influences immediate survival as well as subsequent growth and development of LBW infants. Early nutrition could also influence the longterm neurodevelopmental outcomes. Malnutrition at a vul­ nerable period of brain development has been shown to have deleterious effects in experimental animals. +Term infants with normal birth weight require some assistance for feeding in the immediate postnatal period, but they are able to feed directly from mothers' breast. In contrast, feeding of LBW infants, in particular the preterm infants, is relatively difficult because of the following limitations: +i. Though majority of these infants are born at term, a significant proportion are born premature with inadequate feeding skills. They might not be able to breastfeed and hence would require other methods of feeding such as spoon or gastric tube feeding. +ii. They are prone to have significant illnesses in the first few weeks of life, the underlying condition often precludes enteral feeding. +iii. Preterm infants have higher fluid requirements in the first few days of life due to excessive insensible water loss. + +iv. Since intrauterine accretion occurs mainly in the later part of the third trimester, preterm infants (parti­ cularly those born before 32 weeks of gestation) have low body stores of various nutrients at birth which necessitates supplementation in the postnatal period. +v. Because of the gut immaturity, they are more likely to experience feed intolerance necessitating adequate monitoring and treatment. +Methods +Direct and exclusive breastfeeding is the goal of feeding all LBW infants. However, because of the various limitations, not all LBW infants would be able to accept breastfeeding at least in the initial few days after birth. These infants have to be fed by either spoon/paladai or intragastric tube (gavage feeding). Those babies who cannot accept oral feeds by even these methods would require intravenous (IV) fluids. +The appropriate method of feeding in a given LBW infant is decided based upon the following factors: +• Whether the infant is sick or not; and +• Feeding ability of the infant (which depends upon the gestational maturity). +Level of Sickness +It is essential to categorize LBW infants into two major groups, sick and healthy, before deciding the initial method of feeding. +Sick infants. This group constitutes infants with respiratory distress requiring assisted ventilation, shock, seizures, symptomatic hypoglycemia, electrolyte abnormalities, renal/cardiac failure, surgical conditions of gastrointestinal tract, necrotizing enterocolitis (NEC), hydrops. These infants are usually started on IV fluids. Enteral feeds should be initiated as soon as they are hemodynnically stable +with the choice of feeding method based on the infants' gestation and clinical condition (see below). +It is important to realize that enteral feeding is important even for sick neonates. Oral feeds should not be delayed in them without any valid reason. Even infants with respiratory distress and/or on assisted ventilation can be started on enteral feeds once the acute phase is over and the infants' color, saturation and perfusion have improved. Similarly, sepsis (unless associated with shock/sclerema/ NEC) is not a contraindication for enteral feeding. +Healthy LBW infants. Enteral feeding should be initiated immediately after birth in healthy LBW infants with the appropriate feeding method determined by their oral feeding skills and gestation. + +Ability to Feed +Breastfeeding requires effective sucking, swallowing and a proper coordination between suck/swallow and breathing. These complex skills mature with increasing gestation. A robust sucking pattern is not present until +Newborn Infants - + + + +32-34 weeks gestation. A coordination between sucking, swallowing and breathing does not mature until 34 weeks of gestation. This fully matures by 37 weeks of gestation. The maturation of oral feeding skills and the choice of initial feeding method at different gestational ages are summarized in Table 8.13. +However, it is important to remember that not all infants born at a particular gestation would have same feeding skills. Hence, the ideal way in a given infant would be to evaluate if the feeding skills expected for his/her gestation are present and then decide accordingly (Fig. 8.37). +All stable LBW infants, irrespective of their initial feeding method should be put on their mothers' breast. The immature sucking observed in preterm infants born + +before 34 weeks might not meet their daily fluid and nutritional requirements but helps in rapid maturation of their feeding skills and also improves the milk secretion in their mothers (non-nutritive sucking). +Figs 8.38A and B show the method of paladai and intragastric tube feeding in babies. + +Progression of Oral Feeds +All LBW infants, irrespective of their gestation and birth weight, should ultimately be able to feed directly from the mothers' breast. For preterm LBW infants, the progression to direct and exclusive breastfeeding are summarized in Fig. 8.39. + + + +>34weeks + +.---: Initiate breastfeeding ___, Positioning and attachment are good +---+_, __ +Observe if +Able to suck effectively and long enough +(about 10-15 min) 32-34weeks + + +Yes +Breastfeeding + +No +Start feeds by spoon or paladai + + + +Observe if: +Accepting well without spilling/coughing Able to accept adequate amount + + +28-31 weeks + + + +Yes +Spoon or paladai feeding + +No +Start feeds by orogastric or nasogastric tube + +I Observe if: +vomiting or abdominal distension occurs + + + +Gastric tube feeding Start IV fluids + +Fig. 8.37: Choosing initial methods of feeding + +Table 8.13: Maturation of oral feeding skills and the choice of initial feeding method in LBW infants + +Gestational age, weeks < 28 week + +28-31 week + + +32-34 week + + +>34 week + +Maturation of feedillg skills +Inadequate sucking efforts Lack of propulsive gut motility Sucking bursts develop +Lack of coordination between suck/ swallow and breathing +Slightly mature sucking pattern Coordination between breathing and +swallowing begins Mature sucking pattern +Coordination between breathing and swallowing + + +Initial feeding method Intravenous fluids + +Orogastric or nasogastric tube feeding with occasional spoon or paladai feeding + +Feeding by spoon or paladai + + +Breastfeeding +. E s s e n ti l P e d iatrics _________________________________ +a +. +- +_ +_ +_ +_ +_ +_ +_ _ _ _ _ _ _ _ _ + + + + + + + + + + + + + + + + + + + + + + + + +B + +Figs 8.38A and B: (A) Paladai feeding; (B) Gavage feeding + +Term LBW infants started on IV fluids (because of their sickness) can be put on the breast once they are hemo­ dynamically stable. + +Choice of Milk +All LBW infants, irrespective of their initial feeding method should receive only breast milk. This can be ensured by giving expressed breast milk (mothers' own milk) for those infants fed by paladai or gastric tube. + +Expressed breast milk (EBM). All mothers should be counseled and supported in expressing their own milk for feeding their preterm infants. Expression should ideally be initiated within hours of delivery so that the infant gets the benefits of feeding colostrum. Thereafter, it should be done 2-3 hourly so that the infant is exclusively breastfed and lactation is maintained in the mother. Expressed breast milk can be stored for about 6 hr at room temperature and for 24 hr in refrigerator. +The steps of breast milk expression are given in Fig. 8.35. +Sick mothers/contraindication to breastfeeding. In these rare circumstances, the options available are +i. Formula feeds: +a. Preterm formula in VLBW infants, and +b. Term formula in infants weighing> 1500 g at birth ii. Animal milk, e.g. undiluted cow milk + + + +Infant on IV fluids +! + +11 heodynamically stable + +[ Start trophic feeds by orogastric tube and monitor for feed intolerance +! + +If aepting well +Gradually increase the feed volume, taper and stop IV fluids + +Infant on orogastric tube feeds + +Al 30-32 weeks' gestational age +Try spoon feeds once or twice a day +[ Also put on mother's breast and allow non nutritive suckling If acepting on feeds well + + +Gradually increase the frequency and amount of spoon feeds +Reduce orogastric feeds accordingly + + + +• • +� +Infant on soon or paladai feds + + +Put them on mother's breast before each feed Observe for good attachment and effective sucking +! +J + +If able to breastfed effectively + +Taper and stop spoon feeds once the mother is confident + +Fig. 8.39: Progression of oral feeding in preterm LBW infants. Term and near-term sick infants started on intravenous (IV) fluids can be initiated on breastfeeding once they are hemodynamically stable +Newborn Infants - + + + +Once the mother's condition becomes stable (or the contraindication to breastfeeding no longer exists), these infants should be started on exclusive breastfeeding. + +How Much to Feed? +Infants who are breastfed Infants who are able to suckle effectively at the breast should be breastfed on demand. Small babies usually demand to feed every 2-3 hr, sometimes more frequently. A small infant, who does not +demand to be fed for 3 hr or more, can be offered the breast and encouraged to feed. +Infants who are fed by spoon/paladai or by intra­ +gastric tube It is essential to know how much to feed, the amount of expressed breast milk to be given, for those infants who are on alternative methods of feeding like gavage or spoon feeding. +The daily fluid requirements of neonates have been discussed in the section of fluids and electrolytes. Preterm +infants need more fluids in the initial weeks of life because of the high insensible water loss. It is usual clinical practice to provide VLBW infants (<1500 g) about 80 ml/kg fluids on the first day of life and increase by 10-15 ml/kg/day to a maximum of 160 ml/kg/ day by the end of the first week of life. LBW infants ..1500 g are usually given about 60 ml/kg fluids on the first day of life and fluid intake is increased by about 15-20 ml/kg/day to a maximum of 160 ml/kg/day by the end of the first week of life. After +deciding the total daily fluid requirement, the individual +feed volume to be given every 2 or 3 hr (by OG tube or paladai) can be determined. + +Nutritional Supplementation +LBW infants, especially those who are born preterm, require supplementation of various nutrients to meet their high demands. Since the requirements of VLBW infants +differ significantly from those with birth weights of 1500-2499 g, supplementation regimes for these two groups have been discussed separately. +Supplementation for infants with birth weights of +1500-2499 g These infants are more likely to be born at term or near term gestation (..34 week) and are more likely +to have adequate body stores of most nutrients. Therefore, they do not require multinutrient supplementation (unlike +VLBW infants). However, vitamin D and iron should be supplemented in them (Table 8.14). + +Supplementation in VLBW infants These infants who are usually born before 32-34 week gestation have + +inadequate body stores of most of the nutrients. Since EBM has inadequate amounts of protein, energy, calcium, phosphorus, trace elements (iron, zinc) and vitamins D, E and K, it is often not able to meet the daily recommended intakes of these infants. Hence, these infants need multi­ +nutrient supplementation till they reach term gestation (40 weeks, i.e. until the expected date of delivery). The following nutrients have to be added to the expressed +breast milk in them: +i. Calcium and phosphorus (140-160 mg/kg/day and 70-80 mg/kg/ day respectively for infants on EBM) +ii. Vitamin D (400 IU / day), vitamin B complex and zinc (about 0.5 mg/day) usually in the form of multi­ +vitamin drops +iii. Folate (about 50 µg/kg/day) iv. Iron (2 mg/kg/day) +Multinutrient supplementation can be ensured by one +of the following methods: +i. Supplementing individual nutrients, e.g. calcium, phosphorus, vitamins, etc. These supplements should be added at different times in the day to avoid abnormal increase in the osmolality. +ii. By fortification of expressed breast milk with human milk fortifiers (HMF): Fortification increases the nutrient content of the milk without compromising its other beneficial effects. Experimental studies have shown that the use of fortified human milk results in net nutrient retention that approaches or is greater than expected intrauterine rates of accretion in preterm infants. Preterm VLBW infants fed fortified human milk do not require any supplementation other than iron. +Fortification or supplementation of minerals and +vitamins should be continued only till term gestation (40 weeks) in VLBW infants; after this period, only vitamin D and iron needs to be supplemented (similar to infants with birth weights of ..1500 g). + +Growth Monitoring of LBW Infants +Regular growth monitoring helps in assessing the nutri­ tional status and adequacy of feeding in LBW infants; it also identifies those infants with inadequate weight gain. +All LBW infants should be weighed daily till the time of discharge from the hospital. Other anthropometric parameters such as length and head circumference should be recorded weekly. +Both term and preterm LBW infants tend to lose weight (about 10% and 15% respectively) in the first 7 days of life; they regain their birth weight by 10-14 days. + + +Table 8.14: Nutritional supplements for infants with birth weight between 1500 g and 2499 g + +Nutrients +Vitamin D Iron + + +Method of supplementation +Multivitamin drops or syrup Iron drops or syrup + + +Dose +400 IU/day +2 mg/kg/ day (maximum 15 mg) + +Duration +2 weeks to 1 yr of age +6-8 weeks to 1 yr of age +___s_s_e_n_ti_a _ _P_e_d_ia_tr_ i_cs-------------------------------- +l +E + + +Thereafter, the weight gain should be at least 15-20 g/ kg/ day till a weight of 2-2.5 kg is reached. After this, a gain of 20 to 40 g/ day is considered appropriate. + +Growth charts. Using a growth chart is a simple but effective way to monitor the growth. Serial plotting of weight and other anthropometric indicators in the growth chart allows the individual infant's growth to be compared with a reference standard. It helps in early identification of growth faltering in these infants. +The two postnatal charts that are most commonly used for growth monitoring of preterm VLBW infants are: Wright's and Ehrenkranz' charts. Once the preterm LBW infants reach term gestation (40 week), WHO growth charts should be used for growth monitoring. + +Management of Inadequate Weight Gain +Inadequate weight gain is a common and pertinent problem in LBW infants. It starts at the time of initial admission and continues after discharge resulting in failure to thrive and wasting in the first year of life. The common causes are summarized in Table 8.15. + +Table 8.15: Causes of inadequate weight gain +Inadequate intake +Breastfed infants +Incorrect feeding method (improper positioning or attachment)* +Less frequent breastfeeding, not feeding in the night hours* Infants on spoon or paladai feeds +Incorrect method of feeding* (e.g. excess spilling) Incorrect measurement or calculation +Infrequent feeding* +Not fortifying the milk in VLBW infants +Increased demands +Hypothermia or cold stress* +Chronic illnesses, bronchopulmonary dysplasia Medications such as corticosteroids +*Common causes + +Management of inadequate weight gain consists of the following steps: +i. Proper counseling of mothers and ensuring adequate support for breastfeeding their infants; including an assessment of positioning/ attachment and managing sore or flat nipple. +ii. Explaining the frequency and timing of both breast­ feeding and spoon or pa/adai feeds: Infrequent feeding is one of the commonest causes of inadequate weight gain. Mothers should be properly counseled regarding the frequency and the importance of night feeds. A time-table where mother can fill the timing and amount of feeding is very helpful in ensuring frequent feeding. +iii. Giving EBM by spoon or paladai feeds after breast­ feeding also helps in preterm infants who tire out easily while sucking from the breast. + +iv. Proper demonstration of the correct method of expression of milk and paladai feeding: It is important to observe how the mother gives paladai feeds; the technique and amount of spillage should be noted. This should be followed by a practical demonstration of the proper procedure. +v. Initiating fortification of breast milk when indicated + +Suggested Reading +Nutrition. In: Edmond K, Bahl R (Eds). Optimal feeding of low-birth­ weight infants-Technical Review. World Health Organization 2006; p42 +Sankar MJ, Agarwal R et al. Feeding of low birth weight infants. Indian J Pediatr 2008;75:459-69 + +INFECTIONS IN THE NEONATES +Infection by bacteria constitutes a common morbidity and accounts for nearly one-third of total neonatal deaths. Infections can be superficial and systemic. + +Superficia l Infections +Omphalitis. Any redness or induration around the +umbilicus or pus drainage from it should alert the clinician to omphalitis. Omphalitis starts as a local infection of the umbilicus, usually from unclean handling or application of unclean substances to the cord. It can spread to cause life-threatening systemic sepsis. + +Local infection. When the redness extends to less than 1 cm of surrounding area and there is absence of any sign of sepsis. Local cleaning with antiseptic solution, followed by application of 0.5% gentian violet four times a day till redness subsides would take care + +Severe infection. When area of redness extends beyond 1 cm of surrounding tissue or there are signs of sepsis local therapy plus systemic antibiotic should be started as in management of septicemia. + +Oral thrush. White patchy lesions on the oral mucosa and tongue can occur in healthy newborns. True oral thrush lesions are difficult to wipe off and leave hemorrhagic points when removed. Local nystatin or clotrimazole application four times a day after feed is recommended. + +Conjunctivitis. Conjunctivitis is caused by a variety of bacterial, viral and chalamydial infections. Infection should be differentiated from sticky eyes and blocked nasolacrimal duct. Sticky eyes generally manifests as mucoid discharge without any signs of inflammation and requires cleaning with saline. +Blocked nasolacrimal duct manifests as persistent or intermittent discharge which can be mucopurulent. It requires massage to relieve obstruction and instillation of antibitiocs. Conjunctivitis manifests as purulent discharge and signs of inflammation and requires local instillation +Newborn Infants - + + + +of antibiotics. Gonococcal conjuctivtis can result in blindness and requires timely systemic antibiotics therapy. + +Systemic Infections (Neonatal Sepsis) +When pathogenic organisms gain access into the blood stream, they may cause an overwhelming infection without much localization (septicemia), or may get predominantly localized to the lung (pneumonia) or the meninges (meningitis). Systemic bacterial infections are known by the generic term neonatal sepsis (NNS), which incorporates septicemia, pneumonia and meningitis. + +Etiology +Escherichia coli, Staphylococcus aureus and Klebsiella sp. are the predominant organisms. Organisms like Acinetobacter, Pseudomonas and coagulase negative staphylococci are also important pathogens in hospital acquired infections. + +Early Versus Late Sepsis +Early-onset sepsis (EOS) (less than 72 hr) infections are caused by organisms prevalent in the maternal genital tract or in the delivery area. The predisposing factors include LBW, prolonged rupture of membranes, foul smelling liquor, multiple per vaginal examinations, maternal fever, difficult or prolonged labor and aspiration of meconiurn. EOS frequently manifests as pneumonia and less commonly as septicemia or meningitis. +Late-onset sepsis (LOS) (72 hr or later) infections are caused by the organisms thriving in the external environment of the home or the hospital. The infection is often transmitted through the hands of the care-providers. The presentation is that of septicemia, pneumonia or meningitis. The predisposing factors include LBW, lack of breastfeeding, poor cord care, superficial infections (pyoderma, umbilical sepsis), aspiration of feeds and disruption of skin integrity with needle pricks and use of intravenous fluids. + +Clinical Features +NNS often manifests with vague and ill-defined symptoms and, therefore, requires high index of suspicion for early diagnosis. An early but non-specific manifestation is alteration in the established feeding behavior. The baby, who had been active and sucking normally, refuses to suck and becomes lethargic, or unresponsive. Poor cry, hypothermia, abdominal distension, vomiting and apneic spells are other common manifestations. Diarrhea is uncommon. Fast breathing, chest retractions and grunt indicate pneumonia. Most cases of meningitis do not have any distinct clinical picture per se, making it mandatory to suspect meningitis in all cases suspected of sepsis. Though the presence of excessive or high-pitched crying, fever, seizures, blank look, neck retraction or bulging anterior fontanel are suggestive of meningitis. Shock, bleeding, sclerema and renal failure are indicators of overwhelming sepsis. +Diagnosis of sepsis is fraught with poor specificity. A host of conditions like hypothermia, hyperthermia, hypo­ glycemia, hypoxia, late metabolic acidosis, congestive heart failure and even simple conditions like nasal block may mimic sepsis. A careful clinical examination and relevant investigations are necessary to differentiate these conditions from NNS and avoid unnecessary antibiotics therapy. Babies who are clinically stable can be observed, without admission and intravenous antibodies, while providing good supportive care (Fig. 8.40). + +Investigations +No investigation is required to start treatment in a sick baby who has high probability of sepsis. Blood culture provides definitive diagnosis of NNS and should be taken before starting antimicrobial therapy. After cleaning the skin (alcohol, povidone-iodine and again alcohol, a specimen of 0.5 to 1.0 ml of blood can be taken in a small culture media bottle containing 5 to 10 ml of the liquid broth. + + + + + + +High suspicion of neonatal sepsis j +Baby hemodynamically unstable ++- + +Blood culture +Chest X-ray, if respiratory distress Lumbar puncture, when stable + +• +Low suspicion of neonatal sepsis Baby hemodynamically stable + +Good supportive care +Check and correct: hypothermia, hypoglycemia, polycythemia/anemia, late metabolic acidosis +Assess feeding Perform sepsis screen Re-evaluate + + +Sepsis screen positive or Sepsis screen is negative and clinical suspicion persists clinically sepsis is unlikely +.. +.. + +Start antibiotics Send home with advice to return if worsens + +Fig 8.40: Approach to neonate suspected of sepsis +__ _ssen_ iaiP_ediatr_ic_ _________________________________ +s +E +t +_ +_ +_ +_ _ +_ _ +_ +_ +_ + +Sepsis screen should be performed in equivocal cases. A panel of tests (sepsis screen) consisting of total leukocyte count (TLC; <5000/mm3), absolute neutrophil count (ANC; <1800/mm3), immature to total neutrophil ratio (I/T ratio; more than 20%), CRP (more than 1 mg/dl) and micro ESR (15 mm or more in the first hour) constitutes a useful sepsis screen for clinically doubtful cases. Sepsis screen is considered positive if two of these parameters are positive. Value of sepsis screen is more for exclusion of diagnosis of NNS. +Lumbar puncture should be performed in all cases suspected of NNS except in asymptomatic babies being investigated for maternal risk factors. Table 8.16 provides gestation specific cut offs for values of various parameters in cerebrospinal fluid. + +Table 8.16: Nonnal CSF examination in neonates [ (mean (range) J Test Term Preterm +Cells +7 (0-32) +Leukocytes 9 (0-29) Polrnorphonuclear cells 61% 57% +Protein (mg/dl) 90 (20-170) 115 (65-150) Glucose (mg/ dl) 52 (34-119) 50 (24-63) + + +Treatment +Institution of prompt treatment is essential for ensuring optimum outcome of neonates with sepsis who often reach the health care facilities late and in a critical condition. Supportive care and antibiotics are the two equally important components of treatment. Antibiotics take at least 12 to 24 hr to show any effect, optimum supportive care improves the outcomes in sick septic babies. +Supportive care Good supportive care requires meticulous attention to various aspects: +• Provide warmth; ensure normal temperature (36.5°-37.50C). +• Start oxygen by hood or mask, if the baby is cyanosed or grunting. Provide bag and mask ventilation if breathing is inadequate. Instilling normal saline drops in nostrils may help clear the nasal block. +• Assess peripheral perfusion by palpating peripheral pulses, capillary refill time (normally <2-3 seconds) and skin color. Serial measurement of urine output is helpful for this purpose. Infuse normal saline or Ringer lactate 10 ml/kg over 5-10 minutes, if perfusion is poor. Repeat the same 1-2 times over the next 30-45 minutes, if perfusion continues to be poor. Dopamine and dobu­ tamine may be required to maintain normal perfusion. +• Insert intravenous line. If hypoglycemia is suspected, infuse glucose (10%) 2 ml/kg stat. Do not use glucose boluses routinely. Provide maintenance fluid, electro­ lytes and glucose (4-o mg/kg/min). Add potassium to IV fluids once normal flow of urine has been documented. + +• Ensuring optimal nutrition is extremely helpful in sick babies. Enteral feeds should be initiated early if there is no abdominal distension and baby is hemo­ dynamically stable. Feed mother's milk. Consider parenteral nutrition, if baby is not expected to receive enteral feeds for prolonged period. +• Administer vitamin K 1 mg intramuscularly. +• Transfuse packed cells, if baby has a low hematocrit (less than 35-40%). Do not use blood/plasma transfusion on routine basis for 'boosting' immunity. +Specific care Antimicrobial therapy constitutes the mainstay of treatment of sepsis. In a seriously sick neonate suspected of sepsis, appropriate antibiotics therapy should be initiated without any delay after obtaining blood samples for culture and sepsis screen. One need not await for the results of sepsis screen for antibiotics treatment. However, in a baby who is otherwise stable or suspected of sepsis because of maternal risk factors, it is desirable to await results of sepsis screen before initiation of antibiotics. Since symptoms suggestive of sepsis may be caused by a variety of other illnesses, confirmation of sepsis by sepsis screen may help avoiding unnecessary antibiotics therapy. +Empiric therapy when etiologic agent is not known. The empiric therapy of NNS should cover the major causative pathogens while awaiting reports of culture studies. +Since the antimicrobial spectrum and susceptibility profile is different in different settings, there cannot be a universal policy of empiric regimen. Antibiotics are often used in neonates on the slightest suspicion of sepsis because of the grave and fulminant nature of neonatal sepsis. But unbridled overuse of antibiotics is associated with the serious risk of emergence of resistant strains of pathogens. Most newborn units in the country are facing the problem of overwhelming resistance to practically all antibiotics including third generation cephalosporins. Rational use of antibiotics is, therefore, the responsibility of every physician. +Each treating unit should adopt a suitable policy. Based on changes in the spectrum of etiologic agents and the antibiotics sensitivity pattern, the choice of antibiotics must be periodically reviewed and modified. Table 8.17 provides possible regimen of empiric antibiotics. + +Therapy after an etiologic agent is known. Antimicrobial therapy can be made specific once a positive culture and sensitivity report is available. However, this would be known only after 2-3 days. Even in best institutions, only approximately one-fourth of babies suspected of sepsis have positive blood culture. + +Mode of Administration and Dosage +Antibiotics should preferably be aistered parenterally. In a baby with septicemia or pneumonia (but not meningitis), who has received intravenous ampicillin and +Newborn Infants - + + + + +Clinical situation +Community acquired; resistant strains nlikely +Hospital acquired or when there is a low to moderate probability of resistant strains +Hospital acquired sepsis or when there is a high probability of resistant strains + +Table 8.17: Choice of initial antibiotic therapy Septicemia and pneumonia +Ampicillin or penicillin and gentamicin (First line) +Ampicillin or cloxacillin and amikacin (Second line) + +Cefotaxime and amikacin (Third line) + + +Meningitis +Cefotaxime and gentamicin + +Cefotaxime and amikacin + + +Cefotaxime and amikacin + +Therapy might be modified based on culture report + + +gentamicin initially and is clinically well after 3 days, the physician may consider an individual basis switching over to oral amoxycillin along with single-dose intramuscular gentamicin therapy for the rest of the course. + +Monitoring +Intensive care and monitoring is the key determinant of improved survival of neonates. The elements of monitoring in sepsis are not different from those in other life­ threatening conditions. Proper monitoring of sick babies enables care providers detection of complications at the earliest. The periodicity of documenting the various parameters should be individualized. + +Prognosis +The outcome depends upon weight and maturity of the infant, type of etiologic agent, its antibiotic sensitivity pattern; and adequacy of specific and supportive therapy. The early-onset septicemia carries higher risk of adverse outcomes. The reported mortality rates in neonatal sepsis in various studies from India ranges between 45-58%. The institution of sepsis screen for early detection of infection, judicious and early antimicrobial therapy, close moni­ toring of vital signs and intensive supportive care are the most crucial factors responsible for a better outcome. + +Clinical Features +The illness usually develops after the first week of life. The course may be very fulminant with death occurring in a few hours, mortality rate being around 40-50%. +Clinical manifestations may be described in three stages: Stage 1. Suspected NEC: Unstable temperature, apnea, bradycardia, lethargy, mild abdominal distension, vomiting. Frank or occult, blood may be present in stools. X-ray shows mild intestinal distension. +Stage 2. Clinical signs as similar to stage 1. Bowel sounds are diminished with or without abdominal tenderness. Pneumatosis intestinalis (gas in intestinal wall) and dilatation of intestines are seen on abdominal X-ray (Fig. 8.41). +Stage 3. In addition to the above, the infant is severely sick with hemodynamic instability. There are frank signs of peritonitis with abdominal wall redness. Pneumo­ peritoneum may occur due to intestinal perforation. + +Management +Oral feeding should be withheld. A nasogastric tube is inserted to relieve distension and to aspirate stomach contents. Fluids and electrolytes in adequate quantities should be administered. Parenteral nutrition may be administered. + + +Suggested Reading +Sankar MJ, Agarwal R, Deorari AK, Paul VK. Sepsis in the new­ born. Indian J Pediatr. 2008 Mar;75:261-6 + + +Necrotizing Enterocolitis +Necrotizing enterocolitis (NEC) occurs among smaller premature infants, often those less than 32 week. The clinical picture mimicks neonatal septicemia because of the presence of abdominal distension, apnea, bradycardia, instability of temperature, cyanosis and lethargy. +NEC is believed to result from interaction of several factors such as gut immaturity, mucosal injury due to hypoxia-ischemia, milk feeding and infection. Antenatal steroids and breastfeeding protect against NEC. Delaying enteral feeding does not prevent NEC. + + + + + + + + + + +Fig. 8.41: Necrotizing enterocolitis showing dilated bowel loops and pneumatosis intestinalis (arrows) +__ s_se_n_t_i_i _aP__ed_tiar_i__c ______________________________ _ +s +_ +e +_ + + +The blood, cerebrospinal fluid, urine and stools are cultured. Shock is managed by replacement of fluids and use of vasopressor agents. Plasma and platelet transfusion may be necessary to prevent bleeding tendency. +Perforation is suggested if there is free intra-abdominal gas and liver dullness is obliterated. Surgical intervention is required in these cases. +Sequelae +Intestinal strictures may develop in survivors. These manifest with bloody stools, vomiting and abdominal distention. Shortened bowel leads to malabsorption. + +PERrNATAL ASPHYXfA +Perinatal asphyxia is an insult to the fetus or newborn due to a lack of oxygen (hypoxia) and/or a lack of per­ fusion (ischemia) to various organs. It is often associated with tissue lactic acidosis and hypercarbia. +There is no universally accepted definition of perinatal asphyxia. The American Academy of Pediatrics Committee on Fetus and Newborn has suggested essential criteria (Tables 8.18 and 8.19) for defining perinatal asphyxia. + +Table 8.18: Essential criteria for perinatal asphyxia +Prolonged metabolic or mixed acidemia (pH <7.0) on an umbilical arterial blood sample +Persistence of Apgar score of 0-3 for >5 min +Neurological manifestations, e.g. seizures, coma, hypotonia or hypoxic ischemic encephalopathy (HIE) in the immediate neonatal period +Evidence of multiorgan dysfunction in the immediate neonatal period + +In the absence of such quantification, it is better to use the term 'neonatal depression', which refers to a condition of the infant in the immediate postnatal period (approxi­ mately 1st hr) without making any association with objective evidence. +National Neonatology Forum of India (NNF) and WHO use an Apgar of 0-3 and 4-7, at 1 min, to define severe and moderate birth asphyxia respectively (1985). For the community settings NNF defines asphyxia as absence of cry at 1 min and severe asphyxia as absent or inadequate breathing at five minutes. + +Neuropathology +These differ according to gestation (Table 8.20) and are of the following main types: + + +Table 8.20: Neurological patterns of hypoxic ischemic encephalopathy +Premature newborns +Selective subcortical neuronal necrosis Periventricular leukomalacia +Focal and multifocal ischemic necrosis Periventricular hemorrhage or infarction +Term newborns +Selective cortical neuronal necrosis +Status marmoratus of basal ganglia and thalamus Parasagittal cerebral injury +Focal and multifocal ischemic cerebral necrosis + + +Term +Selective neuronal necrosis involves cerebral cortex, hippocampus, basal ganglia, cerebellum and anterior horn cells of spinal cord. Seen predominantly in term infants and depending on site, this manifests clinically as diminished consciousness, seizures and abnormalities of feeding, breathing, etc. Parasagittal area is a watershed area for many arteries and is vulnerable to ischemia resulting in proximal limb weakness (upper >lower) that later may develop into spastic quadriparesis. Status marmoratus is a variant of selective neuronal necrosis involving basal ganglia and thalamus, having longterm sequelae such as choreoathetosis, spastic quadriparesis and retardation. Focal necroses are commonly thrombo­ embolic and involve the left middle cerebral artery. + +Preterm +Selective neuronal necrosis is rare in preterms; diencephalic neuronal necrosis restricted to thalamus and brainstem with or without hypothalamus and lateral geniculate body is seen. Hypoxia and acidosis followed by hyperoxia demonstrates a unique pattern of injury involving pontine nucleus and subiculum of the hippocampus. +Periventricular leukomalacia (PVL) results from hypoxic-ischemic insult leading to coagulative necrosis and infarction of periventricular white matter that is the watershed area between various arteries. Two areas frequently involved are the posterior white matter, involving the occipital radiation at trigone and anteriorly around the foramen of Munro. Relative sparing of the cerebral cortex is seen due to its rich supply of arteries. Longterm sequelae of PVL include spastic diplegia and + + + + +Central nervous system Pulmonary +Renal Metabolic Gastrointestinal Hematological + +Table 8.19: Multiorgan dysfunction in perinatal asphyxia +Hypoxic ischemic encephalopathy, cerebral edema, longterm neurological sequelae Pulmonary hypertension, meconium aspiration, surfactant disruption +Acute renal failure +Metabolic acidosis, hypoglycemia, hypocalcemia, hyponatremia Necrotizing enterocolitis, hepatic dysfunction Thrombocytopenia, disseminated intravascular coagulation +Newborn Infants - + + + +quadriplegia (lower limbs >upper limbs) and visual impairment. Posthemorrhagic infarcts are usually associated with severe intraventricular bleeds and result from venous infarction due to occlusion of medullary and terminal veins by the large bleed. Other lesions include small infarcts secondary to blocking of end arteries resulting in porencephaly, hydrancephaly or multicysti­ cencephalomalacia. + +Diagnosis and Approach +Hypoxia is an evolving process that starts at the onset of the insult and continues after resuscitation and thereafter manifests in form of sequelae. Management thus depends on which point in this evolution it is detected; with the preventive approach beginning in the prenatal period and then continuing in the form of a long followup much after the stabilization of the initial condition. +A wide spectrum of clinical manifestations is seen depending on the severity of injury. These manifestations change over time and are clinically noted in babies of gestational age more than 36 weeks by classification on the basis of Levenestages of HIE (Table 8.21). +HIE staging helps predict evolution of the disease and longterm outcome. Babies with stage 1 has uniformly good prognosis. Adverse neurological outcomes are present in 20% of babies with stage 2 HIE. In stage 3 HIE, half of the + +neonates die and remaining half tend to have poor neuro­ development outcomes. + +Post-Resuscitation Management of an Asphyxiated Baby (Fig. 8.42) +i. Temperature: Maintain normal temperature of the baby and avoid hyperthermia. In resourceful setting, moderate induced hypothermia (core temperature of 33° to 34°C) reduces the death or severe neuro­ developmental handicap. However, the efficacy and safety of therapeutic hypothermia has not been proved in resource restricted setting (in absence of intensive care). +ii. Oxygen: Both hypoxia and hyperoxia can damage neurons. Oxygen saturations are maintained between 90% to 95%. CO2 concentration in ventilated babies should be maintained between 40 and 50 mm Hg as hypocarbia as well as hypercarbia are detrimental to brain. +iii. Perfusion: Cerebral perfusion in asphyxiated babies is in 'pressure passive' state means there is loss of auto­ regulation and blood supply to the brain is entirely dependant on BPs; it decreased when BP falls and increases when BP rises. Therefore, to maintain normal perfusion pressure, a systemic mean arterial + + +Table 8.21: Levene classification for hypoxic ischemic encephalopathy + +Feature +Consciousness Tone +Seizures Sucking/respiration + +Mild +Irritablity Hypotonia No +Poor suck + +Moderate +Lethargy +viarked hypotonia Yes +Unable to suck + +Severe +Comatose +Severe hypotonia Prolonged +Unable to sustain spontaneous respiration + + +Modified from: Levene MI.The asphyxiated newborn infant. In Levene Ml, Lilford RJ, ed. Fetal and neonatal neurology and neurosurgery. Churchill Livingstone, Edinburgh 1995;405-26 + + + +Need for positive pressure ventilation for ..30 seconds, chest compression or adrenaline +Apgar <7 at 5 minutes + +[±ransfer to NICU a�d monitor the baby +:t +rHemodynamicauy stable; norma1 Abnormal tone, activity, or +one, activity, sensorium and no seizures sensorium and presence of seizures +l +_ +: +- i +Maintain normal body temperature. avoid hyperthermia Maintain normal oxygenation and ventilation by judicious use of oxygen and/or mechanical ventilation Ensure normal perfusion by saline boluse(s) and/or vasopressors, as required +Maintain normal blood glucose by infusion of IV dextrose Treat for seizures, if present +Monitor the baby (neurological and cardiorespiratory examination: renal function) + +Fig 8.42: Post-resuscitation management of an asphyxiated baby +- Essential Pediatrics + + + +pressure of 45-50 mm Hg (term), 35-40 (1-2 kg weight) and 30-35 mm Hg ( <1 kg weight) is required. Judicious use of fluid boluses and use of vasopressors help maintain BP. Hyperviscosity due to poly­ cythemia should be corrected by partial exchange. +iv. Glucose: Levels between 75-100 mg/ dl are recom­ mended. Hyperglycemia enhances cerebral edema and compromise perfusion, while hypoglycemia potentiates excitotoxic damage. Hypoglycemia is commonly seen in asphyxiated infants and the infant must be regularly monitored. +v. Metabolic profile: Hypocalcemia and electrolyte disturbances should be regularly looked for until stabilization of baby and corrected as indicated. +vi. Seizures: 20%-50% of infants with HIE develop sei­ zures during day 1 or 2. Seizures are commonly subtle or focal or multifocal. Metabolic disturbances such as hypoglycemia, hypocalcemia and hyponatremia must be ruled out. Seizures should be treated with anti­ epileptic drugs (AEDs) such as phenobarbitone and phenytoin. The seizures may be intractable initially but usually tend to burn out by 48 hr. Subtle seizures lasting for brief duration need not be treated. +Once the baby is seizure free for 3-4 days, AEDs are stopped in the same order as they were started, except phenobarbitone. Phenobarbitone is stopped at discharge if neurological examination is normal and baby is feeding well on breast. If neurological examination is not normal, then phenobarbitone is continued until one month. At one month if baby is normal neurologically, phenobarbitone is tapered off over a couple of days. If neurological function is abnormal but EEG shows no seizure activity, tapering of phenobarbitone may still be tried. If EEG shows seizure activity, reevaluation is done at 3 months. + +Prognosis +The following features predict a poor outcome: +• Lack of spontaneous respiratory effort within 20-30 minutes of birth is associated with almost uniform mortality +• HIE stage 3 + +• Abnormal neurological findings persisting beyond the first 7-10 days of life +• Oliguria ( <1 ml/kg/ day) during the first 36 hr +Thus all these babies should have regular followup with monitoring of neurodevelopmental milestones to detect any deficits early and to intervene effectively. + +Suggested Reading +Agarwal R Jain A, Deorari AK, Paul VK.Post-resuscitation manage­ ment of asphyxiated neonates. Indian J Pediatr 2008;75:175--80 + +RESPIRATORY DISTRESS +Respiratory distress in the neonate is a common problem and it can be a serious neonatal emergency. Respiratory distress is said to be present when tachypnea (RR >60 per min) is accompanied by chest retractions and or grunt. It can be due to respiratory (Table 8.22) and non-respiratory causes (Table 8.23). Early recognition and prompt treatment is essential to improve outcomes. + +Approach +Respiratory distress in a neonate can be recognized by the presence of varying combinations of tachypnea (RR >60/min), chest retractions, grunting, flaring of ala enasi and cyanosis. The gestation, age at onset, severity of distress and presence of associated clinical features help in arriving at diagnosis. It should be noted that chest retractions are mild or absent in respiratory distress due to non-respiratory causes. + +Respiratory causes. Conditions listed in Tables 8.22 and 8.23 can occur both in preterm and term babies. However, if a preterm baby has respiratory distress within the first few hours of life the most likely cause is respiratory distress syndrome (RDS). Similarly if a term baby born to a mother with meconium stained liquor develops respiratory distress within the first 24 hr, the most likely cause is meconium aspiration syndrome (MAS). A term baby with +uncomplicated birth developing tachypnea in the first few +hours of birth is likely to have transient tachypnea of newborn. Presence of suprasternal recessions with or without stridor indicates upper airway obstruction. + + +Table 8.22: Pulmonary causes of respiratory distress + +Cause +Respiratory distress syndrome Meconium aspiration syndrome + +Pneumonia +Transient tachypnea of newborn Persistent pulmonary hypertension Pneumothorax +Tracheoesophageal fistula, diaphragmatic hernia, lobar emphysema + +Time of onset +First 6 hr of life First few hr of life + +Any age +First 6 hr after birth Any age +Any age Any age + +Remarks +Common in preterm neonates +Common in term, post-term and small for date babies; history of meconium stained liquor +Often bacterial +Tachypnea with minimal distress; lasts for 48-72 hr Severe distress; cyanosis +Sudden deterioration; usually during assisted ventilation May show associated malformations; polyhydramnios in +esophageal atresia +Newborn Infants - + + +Table 8.23: Non-pulmonary causes of rapid breathing Clinical Features + +Cardiac + +Metabolic + +Central nervous system +Chest wall + + +Congestive heart failure; congenital heart disease +Hypothermia, hypoglycemia, metabolic acidosis +Asphyxia, cerebral edema, hemorrhage + +Asphyxiating thoracic dystrophy, Werdnig-Hoffman disease + +Respiratory distress usually occurs within the first 6 hr of life. Clinical features include tachypnea, retractions, grunting, cyanosis and decreased air entry. Diagnosis can be confirmed by chest X-ray. Radiological features include reticulogranular pattern, ground glass opacity, low lung volume, air bronchograrn (Fig. 8.43) and white out lungs in severe disease. + + + +Cardiac disease. Cardiac etiology for respiratory distress should be suspected if a neonate with distress has cyanosis or hepatomegaly. Congenital heart disease and cardio­ myopathies or rhythm disorders can present as congestive cardiac failure in the neonatal period. Transposition of great vessels (TGV) and hypoplastic left heart syndrome usually present on day one with progressive distress. Most other cardiac conditions present after the first week of life. A preterm neonate having a systolic murmur with tachy­ pnea and hepatomegaly is likely to have patent ductus arteriosus (PDA). + +Neurological causes. Neonates with birth asphyxia, cerebral hemorrhage, or meningitis can present with tachypnea and respiratory distress. These neonates are usually lethargic with poor neonatal reflexes. + + +Respiratory Distress Syndrome (RDS) or Hyaline Membrane Disease (HMD) +RDS is common in preterm babies less than 34 weeks of gestation. The overall incidence is 10-15% but can be as high as 80% in neonates <28 weeks. In addition to prematurity, asphyxia, acidosis, maternal diabetes and cesarean section can increase the risk of RDS. + +Etiopathogenesis +In RDS, the basic abnormality is surfactant deficiency. Surfactant is a lipoprotein containing phospholipids like phosphatidylcholine and phosphatidylglycerol and proteins. Surfactant is produced by type II alveolar cells of lungs and helps reduce surface tension in the alveoli. In the absence of surfactant, surface tension increases and alveoli tend to collapse during expiration. During inspira­ tion more negative pressure is needed to keep alveoli patent. There is inadequate oxygenation and increased work of breathing. Hypoxernia and acidosis result in pul­ monary vasoconstriction and right to left shunting across the forarnen ovale. This worsens the hypoxernia and the neonate eventually goes into respiratory failure. Ischernic damage to the alveoli causes transudation of proteins into the alveoli that forms hyaline membrane. Surfactant pro­ duction starts around 20 weeks of life and peaks at 35 week gestation. Therefore any neonate less than 35 week is prone to develop RDS. + + +Fig. 8.43: Moderate to severe hyaline membrane disease. Note homogenous opacification of lungs obscuring heart borders and presence of air bronchogram (arrows) + +Management +Neonates suspected to have RDS need to be cared for in neonatal intensive care unit with IV fluids and oxygen. Mild to moderate RDS can be managed with continuous positive airway pressure (CPAP). CPAP is a non invasive modality of support where a continuous distending pressure (5-7 cm of water) is applied at nostril level to keep the alveoli open in a spontaneously breathing baby (Fig. 8.44). This is an excellent modality of respiratory support which minimizes lung injury and other compli­ cations such as air leak and sepsis. Preterm babies developing severe RDS often require mechanical ventilation. Preterm babies are at risk of lung injury by excessive pressure and high oxygen. High saturations of oxygen (above 95%) can produce retinopathy of pre­ maturity (ROP) which can blind the infant. +Since surfactant deficiency is the basis of RDS, exogenous surfactant is recommended as the treatment of choice in neonates with RDS. Surfactant is indicated in all neonates with moderate to severe RDS. The route of administration is intra tracheal. It can be given as a rescue treatment (when RDS actually develops) or prophylac­ tically (all neonates less than 28 weeks irrespective of presence or absence of RDS). Surfactant decreases duration +-.:::::;::,,;,:.:,:,:,;.: �rl:..____________________________ +nt +e la +l +e la +Ess P d t cs + +distress in the first few hours of life that often deteriorates in subsequent 24-48 hr. If untreated, distress can progress to respiratory failure. Complications include pneumo­ thorax, other air leak syndromes (pneumopericardiurn, pneumomediastinurn) and persistent pulmonary hyper­ tension. Chest X-ray shows bilateral heterogeneous opacities, areas of hyperexpansion and atelectesis and air leak (Fig. 8.45). + + + + + + +Fig. 8.44: Continuous positive airway pressure being provided to a preterm baby + +and level of support of ventilation in neonates and therefore improves outcome. Many babies can be INtubated, given SURfactant and rapidly Extubated (lnSurE approach) to CPAP (Fig. 8.44). This avoids the need for mechanical ventilation in many neonates. +RDS has generally a good prognosis if managed appropriately. Survival is as high as 90% in very low birth weight babies (<1500 g). In the absence of ventilatory support, most neonates with severe disease will die. + +Prevention of RDS +Administration of antenatal steroids to mothers in preterm labor ( <35 week) has been a major breakthrough in management of preterm infants. Antenatal steroids reduces RDS, intraventricular hemorrhage and mortality in preterm neonates (Table 8.24). + +Table 8.24: Benefits of administering antenatal glucocortlcoids +Reduction in neonatal mortality by 40% Reduction in respiratory distress by 50% Reduction in intraventricular hemorrhage by 50% +Reduction in occurrence of patent ductus arteriosus, necrotizing enterocolitis, hemodynamic instability + +Meconium Aspiratrion Syndrome (MAS) +Meconiurn staining of amniotic fluid (MSAF) occur in 10%-14% of pregnancies. Neonates born through MSAF can aspirate the meconium into the lungs and develop respiratory distress (meconium aspiration syndrome; MAS). Aspirated meconium can block the large and small airway causing areas of atelectasis and emphysema which can progress to develop air leak syndromes like pneumo­ thorax. Presence of atelectasis and emphysema can cause ventilation perfusion mismatch in these babies that can progress to respiratory failure. Meconium also induces chemical pneumonitis. + +Clinical Features and Course +MAS usually occurs in term or post term babies and small for dates babies. Infants usually develops respiratory + + + + + + + + + + + +Fig. 8.45: Meconium aspiration syndrome. Note hyperexpansion of lungs and heterogeneous opacities in right lung + +Management +Clinical course in these babies can be complicated by severe pulmonary hypertension. A good supportive care in terms of maintenance of normal body temperature, blood glucose and calcium levels, ensuring analgesia and avoiding unnecessary fiddling pay good dividends. Oxygenation and ventilation is maintained by judicious use of oxygen and mechanical ventilation. With ventilatory support, 60-70% neonates survive, but in the absence of ventilatory support, mortality is high in severe disease. + +Persistent Pulmonary Hypertension (PPHN) +It is caused by a persistent elevation in pulmonary vascular resistance resulting in right to left shunt across the forarnen ovale and/ or ductus. The disease is more common in term and post-term babies and occurs as a result of persistent hypoxia and acidosis. Hypoxia and hypercarbia cause pulmonary vasoconstriction. This increases pulmonary vascular pressure and results in right to left shunting. +Common causes include asphyxia, respiratory distress due to MAS, RDS, diaphragmatic hernia, etc. Primary pulmonary hypertension can also occur because of an abnormal pulmonary vasculature secondary to chronic intrauterine hypoxia. +The neonate usually presents with severe respiratory distress and cyanosis. It is often difficult to differentiate PPHN from cyanotic congenital heart disease. Echo­ cardiography helps in ruling out congenital heart disease and may demonstrate right to left shunt across the forarnen ovale. +I ----------------------------------Ne_ b_o_r__i f_a__s__ +n +t +n +n +_ +w + + +Ventilatory support is mandatory. Nitric oxide, a selective pulmonary vasodilator is an effective therapy. + +Pneumonia +Pneumonia is a common cause of respiratory distress in +both term and preterm babies and is caused by bacteria such E. coli, S. aureus and K. pneumoniae. Neonatal pneumonia may be due to aspiration or occasionally due to viral or fungal infection. Though group B streptococcal pneumonia is common in the West, it is uncommonly reported in India. +The neonate has features suggestive of sepsis in addition +to respiratory distress. Chest X-ray shows pneumonia (Fig. 8.46), blood counts are raised and blood culture may be positive. Treatment includes supportive care and specific antibiotic therapy. Ampicillin or cloxacillin with gentamicin is usually used. If the pneumonia is due to hospital acquired infection, antibiotics like cephalosporins with amikacin may have to be used. + + + + + + + + + + + + + + + + + +Fig. 8.46: Pneumonia. Note heterogeneous opacities in both the lung fields + +Transient Tachypnea of Newborn (TTN) +Transient tachypnea of the newborn is a benign self­ limiting disease occurring usually in term neonates and is due to delayed clearance of lung fluid. These babies have tachypnea with minimal or no respiratory distress. Chest X-ray may show hyperexpanded lung fields, prominent vascular marking and prominent interlobar fissure (Fig. 8.47). Oxygen treatment is often adequate. Prognosis is excellent. + +Surgical Problems +Tracheoesophageal fistula (TEF) should be suspected in any neonate with excessive frothing. Diagnosis can be confirmed by a plain X-ray with a red rubber catheter (not infant feeding tube, it is soft and gets coiled up) inserted in stomach; the catheter generally stops at 10th thoracic + + + + + + + + + + + + + + + + +Fig. 8.47: Transient tachypnea of newborn. Note hyperinflated lungs, prominent bronchovascular markings and horizontal fissure (arrow) + +vertebrae in presence of esophageal atresia. Presence of gastric bubble suggest concomitant TEF. +Diaphragmatic hernia should be suspected in any neonates who has severe respiratory distress and has a scaphoid abdomen. This condition can be detected during antenatal ultrasonography. Chest X-ray shows presence of bowel loops in the thoracic cavity. +Chronic Lung D sease (CLO) or Bronchopulmonary Dysplasla (BPD) +i +CLD occurs because of barotrauma and oxygen toxicity that causes damage to the alveolar cells, interstitium and blood vessels. Inflammatory mediators are released and there is increased permeability causing leakage of water and protein. In later stages, there is fibrosis and cellular hyperplasia. Severe lung damage leads to respiratory failure. These babies continue to require prolonged oxygen therapy or ventilatory support. + +Pneumothorax +Presence of air in the pleural cavity (pneumothorax) is most common in babies with meconium aspiration syndrome and those being ventilated (Fig. 8.48). Transillumination of the chest can help in diagnosis. Needle aspiration or chest tube drainage is a life saving procedure in this situation. + +Apnea +Apnea is defined as cessation of respiration for 20 seconds with or without bradycardia and cyanosis or for shorter periods if it is associated with cyanosis or bradycardia. Apnea is a common problem in preterm neonates. It could be central, obstructive or mixed. +Apnea of prematurity occurs in preterm neonates between the second to fifth days of life and is because of the immaturity of the developing brain. Central apnea can also occur because of pathological causes like sepsis, metabolic problems (hypoglycemia, hypocalcemia), +__ _s_s_e_n_ t_ a_l_P_e_d_ i_a _tr_ c_ ________________________________ +i +i +s +E + + + + + + + + + + + + + + + + + + +Fig. 8.48: Tension pneumothorax on right side displacing the mediastinum and pushing down the diaphragm + +temperature instability, respiratory distress, anemia and polycythemia. Obstructive apnea can occur because of block to the airway by secretion or improper neck positioning. +Treatment is supportive and involves correction of underlying cause. Apnea of prematurity is treated with aminophylline or caffeine. Prognosis is good in apnea of prematurity. In other cases it depends on the underlying cause. + +Suggested Reading +Bhutani I<. Differential diagnosis of neonatal respiratory disorders. In: Intensive of the Fetus and Neonate. Ed Spitzer AR. Mosby Year Book 1996;494-505 +Greenough A, Roberton MRC. Respiratory distress syndrome. In: Neonatal Respiratory Disorders. Eds Greenough A, Roberton NRC, Milner AD. Arnold 1996;238-79 +Singh M, Deorari AK. Pneumonia in newborn babies.Indian J Pediatr 1995; 62:293-306 + +JAUNDICE +Jaundice is an important problem in the first week of life. High bilirubin levels may be toxic to the developing central nervous system and may cause neurological impairment even in term newborns. Nearly 60% of term newborn becomes visibly jaundiced in the first week of life. In most cases, it is benign and no intervention is required. Approximately 5-10% of them have clinically significant jaundice requiring use of phototherapy or other therapeutic options. + +Physiological Versus Pathological Jaundice +Physiological jaundice represents physiological immaturity of the neonates to handle increased bilirubin production. Visible jaundice usually appears between 24-72 hr of age. + +Total serum bilirubin (TSB) level usually peaks by 3 days of age and then falls in term neonates. TSB levels are below the designated cut-offs for phototherapy. It does not require any treatment. +Pathological jaundice is referred to as an elevation of TSB levels to the extent where treatment of jaundice is more likely to result into benefit than harm. There is no clear cut demarcation between pathological and physio­ logical jaundice. TSB levels have been arbitrarily defined as pathological if it exceeds 5 mg/ dl on first day, 10 mg/ dl on second day, or 15 mg/ dl thereafter in term babies. Such jaundice warrants investigation for the cause and therapeutic intervention such as phototherapy. Appearance of jaundice within 24 hr, TSB levels above the expected normal range, presence of clinical jaundice beyond 3 weeks and conjugated bilirubin (dark urine staining the nappy) would be categorized under this category. + +Breastfeeding Jaundice +Exclusively breastfed infants have a different pattern of physiological jaundice as compared to artificially-fed babies. Jaundice in breastfed babies usually appears between 24-72 hr of age, peaks by 5-15 days of life and disappears by the third week of life. One-third of all breastfed babies are detected to have mild clinical jaundice in the third week of life, which may persist into the 2nd to 3rd month of life in a few babies. This increased frequency of jaundice in breastfed babies is not related to characteristics of breast milk but rather to inadequate breastfeeding (breastfeeding jaundice). Ensuring optimum breastfeeding would help decrease this kind of jaundice. + +Breast Milk Jaundice +Approximately 2-4% of exclusively breastfed term babies have jaundice in excess of 10 mg/ dl beyond third-fourth weeks of life. These babies should be investigated for prolonged jaundice. A diagnosis of breast milk jaundice should be considered if this is unconjugated (not staining nappies); and other causes for prolongation such as inadequate feeding, continuing hemolysis, extravasated blood, G6PD deficiency and hypothyroidism have been ruled out. Mothers should be advised to continue breastfeeding at frequent intervals and TSB levels usually decline over a period of time. Some babies may require phototherapy. Breastfeeding should not be stopped either for diagnosis or treatment of breast milk jaundice. + +Clinical Estimation +Originally described by Kramer, dermal staining of bilirubin may be used as a clinical guide to the level of jaundice. Dermal staining in newborn progresses in a cephalocaudal direction. The newborn should be examined in good daylight. The skin of forehead, chest, abdomen, thighs, legs, palms and soles should be blanched with digital pressure and the underlying color of skin and subcutaneous tissue should be noted. +Newborn Infants - + + + +Serum levels of total bilirubin are approximately 4-6 mg/dl (zone 1), 6-8 mg/dl (zone 2), 8-12 mg/dl (zone 3), 12-14 mg/dl (zone 4) and >15 mg/dl (zone 5) (Fig. 8.49). Yellow staining of palms and soles is a danger sign and requires urgent serum bilirubin estimation and further management. In general, the estimation ofbilirubin levels by dermal zones is unreliable particularly at higher TSB levels, after phototherapy and when it is carried out by an inexperienced observer. Total serum bilirubin can be assessed non invasively by a transcutaneous handheld device. + + + + + + + + + + + + + + + + + + + + +Fig. 8.49: Dermal zones for estimation of total serum bilirubin levels + +Measurement of Billrubin Levels +Newborns detected to have yellow discoloration of the skin beyond the legs, or when their clinically assessed TSB levels approach phototherapy range, should have lab confirmation of total serum bilirubin. TSB assessment has a marked interlaboratory variability. + +Causes +Important causes of jaundice in neonates include: +i. Hemolytic: Rh incompatibility, ABO incompatability, G6PD deficiency, thalassemias, hereditary sphero­ cytosis +ii. Non-hemolytic: prematurity, extravasated blood, inadequate feeding, polycythenia, idiopathic, breast milk jaundice +Risk factors for development of severe hyper biliru­ binernia include: +i. Jaundice observed in the first 24 hr +ii. Blood group incompatibility with positive direct antiglobulin test, other known hemolytic disease (e.g. G6PD deficiency). + +iii. Gestational age 35-36 weeks. +iv. Previous sibling received phototherapy. v. Cephalohematoma or significant bruising. +vi. If breastfeeding is inadequate with excessive weight loss + +Approach to a Jaundiced Neonate +All the neonates should be visually inspected for jaundice every 12 hr during initial 3 to 5 days of life (Fig. 8.50). Transcutaneous bilirubin (TcB) can be used as an aid for initial screening of infants. Visual assessment (when performed properly) and TcB have reasonable sensitivity for initial assessment of jaundice. +As a first step, serious jaundice should be ruled out. Phototherapy should be initiated if the infant meets the criteria for serious jaundice. Total serum bilirubin should be determined subsequently in these infants to determine further course of action. + +Management Investigations +The aim of performing investigations is to confirm the level of jaundice, identify the cause and follow response to treatment. + +First line +• Total serum bilirubin (and its fractions, if jaundice is prolonged or there is yellow staining of nappies): All cases with suspected pathological levels either clinically or by trancutaneous measurements need confirmation by blood examination of serum bilirubin levels. +• Blood groups of mother and baby (if the mother is 'O' or Rh negative): detects any incompatibility +• Peripheral smear: evidence of hemolysis +Second line +• Direct Coombs test: detects presence of antibody coating on fetal RBC +• Hematocrit: decreased in hemolysis +• Reticulocyte count: increased in hemolysis • G6PD levels in RBC +• Others: sepsis screen; thyroid function test; urine for reducing substances to rule out galactosernia; specific enzyme/genetic studies for Crigler-Najjar, Gilbert and other genetic enzyme deficiencies + +Physiological Jaundice +The parents should be explained about the benign nature of jaundice. The mother should be encouraged to breastfeed frequently and exclusively. Mother should be told to bring the baby to the hospital if the baby looks deep yellow or palms and soles have yellow staining. There is no use to expose the baby to direct sunlight to reduce hyperbilirubinemia. +Any newborn discharged prior to 72 hr of life should be evaluated again in the next 48 hr for assessment of adequacy of breastfeeding and progression of jaundice. +__ _s s_ _nt 1a_1_P_ _d 1a t _r1c _____________________________ +_ +s +e +_ +E +e +_ +_ +_ + +Perform visual assessment of Jaundice: every 12 h during initial 3 to 5 days of life. +visual assessement can be supplemented with transcutaneous bilirubinometry (TcB), if available + +Step 1: Does the baby have serious jaundice*? + + + + +Step 2: Does the infant have significant jaundice to require serum billirubin measurement'? + + + + +Measure serum bilirubin and determine if baby requires Continued observation every 12 hr phototherapy or exchange transfusion (refer to Table 8.25) + + +Step 3: Determine the cause of jaundice and provide supportive and followup care + + +*Serious jaundice +a. Presence of visible jaundice in first 24 hr +b. Yellow palms and soles anytime +c. Signs of acute bilirubln encephalopathy or kernicterus: hypertonia, abnormal posturing such as arching, retrocollis, opisthotonus or convulsion, fever, high pitched cry + + +Measure serum blllrubln If a. Jaundice in first 24 hr +b. Beyond 24 hr: If on visual assessment or by transcutaneous bilirubinometry, total bilirubin Is likely to be more than +12-14 mg/di or approaching phototherapy range or beyond c. If you are unsure about visual assessment + + +Fig 8.50: Approach to an infant with jaundice +25 + + +Pathological Jaundice +Term and near term neonates The American Academy of Pediatrics (AAP), has laid down criteria for managing babies with elevated serum bilirubin (Figs 8.51 for phototherapy and 8.52 for exchange transfusion). Both the Figs have age in hours on the X-axis and TSB levels on Y-axis. There are three curves on each Fig. representing three risk categories of babies defined by gestation and other risk factors. Risk factor refer to hemolysis, asphyxia, acidosis, low albumin level, G6PD deficiency, hypothemia and sickness. + +25 + +� 20 +r + +-� 15 E 10 + +5 +� +F +0 +Birth + + +1 + + + + + + + +24 h 48 h + + + + + +i +72 h 96 h +Age + + + +20 + +15 1 +10 + +5 + +0 +5 days 6 days 7 days + + + +Preterm neonates Table 8.25 provides cutoffs for exchange transfusion and phototherapy in preterm neonates below 35 weeks of gestation. + +Table 8.25: Suggested TSB cut-offs for phototherapy and exchange transfusion In pretern Infants <35 weeks +Gestation (completed Phototherapy Exchange transfusion weeks) +<28 5-6 11-14 28 to 29 6-8 12-14 30 to 31 8-10 13-16 32 to 33 10-12 15-18 34 12-14 17-19 + +Use postmenstrual age (for phototherapy for example, when a 29 week infant is 7 days old, use the TSB level for 30 weeks). +(Adapted with permission from Maisels et al, Jour Perinatal, 2012) + +Fig. 8.51: Guidelines for phototherapy in hospitalized infants of 35 or more weeks' gestation. - Infants at lower risk (>38 week and well) - Infants at medium risk (>38 week + risk factors or 35-37 6/7 week and well) - Infants at higher risk (35-37 6/7 week + risk factors) + +Prolonged Jaundice Beyond 3 Weeks +This is defined as persistence of significant jaundice (10 mg/dl) beyond three weeks in a term baby. The common causes include inadequate feeding, breast milk jaundice, extravasated blood (cephalohematoma), ongoing hemolytic disease, G6PD deficiency and hypothyroidism. One should rule out cholestasis by noting the urine and stool color and checking the level of direct bilirubin. If the baby has dark urine or significant jaundice, investigations should be initiated to rule out: +-----------------------------------N_e_w_b_o_r_nr_nf_a_n_t_s _ + + +30-------------------,-30 + +'6 +f +25 25 +C: +r +ZS +i +.0 20 20� +� +E +E +2 +� 15 15 +ll +� +I + +10 10 +Birth 24 h 48 h 72 h 96 h 5 days 6 days 7 days Age +Fig. 8.52: Guidelines for exchange transfusion in infants 35 or more weeks' gestation. - Infants at lower risk (> 38 week and well) - Infants at medium risk(> 38 week + risk factors or 35-37 6/7 week and well) - Infants at higher risk (35-37 6/7 week + risk factors) (Adapted from AAP 2004) + + +i. Cholestasis (stool color, urine color, direct and indirect bilirubin levels) +ii. Ongoing hemolysis, G6PD screen iii. Hypothyroidism +iv. Urinary tract infection + +Phototherapy Phototherapy remains the mainstay of treating hyperbilirubinemia in neonates. Photocopy is highly effective and carries an excellent safety track record of over 50 yr. It acts by converting insoluble bilirubin (unconjugated) into soluble isomers that can be excreted in urine and feces. Many review articles have provided detailed discussion on phototherapy related issues. The bilirubin molecule isomerizes to harmless forms under blue-green light (460-490 nm); and the light sources having high irradiance in this particular wavelength range are more effective than the others. +For phototherapy to be effective, bilirubin needs to be present in skin so there is no role for prophylactic phototherapy. Phototherapy acts by several ways: +• Configurational isomerization: Here the Z-isomers of bilirubin are converted into E-isomers. The reaction is instantaneous upon exposure to light but reversible as bilirubin reaches into the bile duct. After exposure of 8-12 hr of phototherapy, this constitutes about 25% of TSB, which is nontoxic. Since this is excreted slowly from body this is not a major mechanism for decrease in TSB. +• Structural isomerization: This is an irreversible reaction where the bilirubin is converted into lumirubin. The reaction is directly proportional to dose of photo­ therapy. This product forms 2-6% of TSB which is rapidly excreted from body thus is mainly responsible for phototherapy induced decline in TSB. +• Photo oxidation: This is a minor reaction, where photo-products are excreted in urine. + + +Types of phototherapy lights. The phototherapy units available in the market have a variety of light sources that include florescent lamps of different colors (cool white, blue, green, blue-green or turquoise) and shapes (straight or U-shaped commonly referred as compact florescent lamps, i.e. CFL), halogen bulbs, high intensity light emitting diodes (LED) and fibro-optic light sources. +With the easy availability and low cost in India, CFL phototherapy is being most commonly used device. Often, CFL devices have four blue and two white (for exami­ nation purpose) CFLs but this combination can be replaced with 6 blue CFLs in order to increase the irradiance output. +In last couple of years, blue LED is making inroads in neonatal practice and has been found to at least equally effective. LED has advantage of long life (up to 50,000 hr) and is capable of delivering higher irradiance than CFL lamps. +Maximizing the eficacy of phototherapy. The irradiance of phototherapy lights should be periodically measured and a minimum level of 30 microW /cm2/nm in the wave­ length range of 460 to 490 nm must be ensured. The lamps should be changed if the lamps are flickering or ends are blackened, if irradiance falls below the specified level or as per the recommendation of manufacturers. +Expose maximal surface area of the baby (Fig. 8.53). Avoid blocking the lights by any equipment (e.g. radiant warmer), a large diaper or eye patch, a cap or hat, tape, dressing or electrode, etc. ensure good hydration and nutrition of the baby. Make sure that light falls on the baby perpendicularly if the baby is in incubator. Minimize interruption of phototherapy during feeding sessions or procedures. +Administering phototherapy. Make sure that ambient room temperature is optimum 25° to 28°C to prevent hypothermia or hyperthermia in the baby. Remove all clothes of the +baby except the diaper. Cover the baby's eyes with an eye + + + + + + + + + + + + + + + + +Fig. 8.53: A jaundiced baby receiving phototherapy with two overhead units and biliblanket pad (arrow) +__ E_ss_e_n_tia i _P_e_dia_tri_c_ _______________________________ +s +_ +_ +_ +_ +_ +_ + +patch, ensuring that it does not block baby's nostrils. Place the naked baby under the lights in a cot or bassinet if weight is more than 2 kg or in an incubator or radiant warmer if the baby is small ( <2 kg). Keep the distance between baby and light 30 to 45 cm (or as per manufacturer recommendation). +Ensure optimum breastfeeding. Baby can be taken out for breastfeeding sessions and the eye patch can be removed for better mother-infant interaction. However, minimize interruption to enhance effectiveness of phototherapy. There is no need to supplement or replace breast milk with any other types of feed or fluid (e.g. breast milk substitute, water, sugar water, etc.). +Monitoring and stopping phototherapy. Monitor temperature of the baby every 2 to 4 hr. Measure TSB level every 12 to 24 hr. +Discontinue phototherapy once two TSB values 12 hr apart fall below current age specific cut offs. The infant should be monitored clinically for rebound bilirubin rise within 24 hr after stopping phototherapy for babies with hemolytic disorders. + +Exchange Transfusion +Double volume exchange transfusion (DVET) should be performed if the TSB levels reach to age specific cut-off for exchange transfusion (Fig. 8.52 and Table 8.25) or the infant shows signs ofbilirubin encephalopathy irrespective of TSB levels. +Indications for DVET at birth in infants with Rh isoimmunization include: +i. Cord bilirubin is 5 mg/ dl or more ii. Cord Hb is 10 g/dl or less +At birth, if a baby shows signs of hydrops or cardiac decompensation in presence of low PCV (<35%), partial exchange transfusion with 50 ml/kg of packed red blood cells should be done to quickly restore oxygen carrying capacity of blood. +The ET should be performed by pull and push technique using umbilical venous route. Umbilical catheter should be inserted just enough to get free flow of blood. + +Followup +Babies with serum bilirubin ?.20 mg/dl and those who require exchange transfusion should be kept under followup in the high-risk clinic for neurodevelopmental outcome. Hearing assessment (BERA) should be done at 3 months of age. With prompt treatment, even very elevated serum bilirubin levels within the range of 25 to 29 mg/dl are not likely to result in longterm adverse effects on neurodevelopment. + +Prevention +• Antenatal investigation should include maternal blood grouping. Rh positive baby born to a Rh negative mother is at higher risk for hyperbilirubinemia and + +requires greater monitoring. Anti D (RhoGam) injection after first obstetrical event ensures decreased risk of sensitization in future pregnancies. +• Ensuring adequate breastfeeding +• Parent education regarding danger signs should include yellowish discoloration below knees and elbows or persistent jaundice beyond 15 days as reason for immediate checkup by health personnel. +• High risk babies such as ones with large cephalo­ hematoma or family history of jaundice should be followed up after 2-3 days of discharge. + +CONGENITAL MALFORMATIONS +Tracheoesophageal Fistula (TEF) +Upper part of esophagus is developed from retro­ pharyngeal segment and the lower part from pregastric segment of the first part of the primitive gut. At four weeks of gestation, the laryngotracheal groove is formed. Later, two longitudinal furrows develop to separate the respiratory primordium from the esophagus. Deviation or altered cellular growth in this septum results in formation of tracheoesophageal fistulae. Incidence is 1 in 4000 live births. In the most common variety (over 80% of cases), the upper part of the esophagus ends blindly and the lower part is connected to the trachea by a fistula. + +Clinical Features +The presence of maternal polyhydramnois and single umbilical artery should alert the health provider to look for atresia of the upper digestive tract. Association of congenital anomalies of vertebrae, anorectal region, heart, kidneys or limbs should also arouse suspicion. The newborn baby has excessive drooling soon after birth with frothing. There is choking and cyanosis on feeding. Overflow of milk and saliva from esophagus and regurgitation of secretion through the fistulous tract (when present) into the lungs results in aspiration pneumonia. + +Diagnosis +A stiff red rubber catheter cannot be passed into stomach as it gets arrested at a distance of 7-10 cm from the mouth (Fig. 8.54). A skiagram may be obtained after instilling 1-2 ml of air through the catheter. It is not advisable to use barium as a contrast material since it may be aspirated in lungs. +On X-ray, an air bubble is seen in the stomach if there is communication between the lower part of the esopagus and trachea, which occurs in the commonest variety of tracheoesophageal fistula. In other variety, wherein there is no communication of esophagus and trachea, there will be no gas in stomach. + +Management +The baby should be nursed supine or in an upright position and esophageal pouch should be gently sucked +-------------------------------N_e_w_b_o_r_n_i_n_f_a_n .ts .- + + + + + + + + + + + + + + + + + + +Fig. 8.54: Esophageal atresia with tracheoesophageal fistula. Note the red rubber catheter stopping at T4 level (arrow 1 ). There is a double gas bubble sign indicating presence of concomitant duodenal atresia (arrow 2) + +every five minutes, or continuously using a slow suction device. Intravenous fluids should be administered and infection, if any should be treated. Surgical repair should be undertaken as early as possible. + +Anorectal Malformation + +A variety of anorectal anomalies have been described. These may be anatomically classified as high, intermediate or low. The position is determined by the relation of terminal part of bowel to the puborectalis sling. High or intermediate lesions are more common in males. Anal stenosis or covered anus, anocutaneous fistulae are common in both sexes. Anovestibularfistula (low lesion) in females and anorectal agenesis with rectoprostatic urethral fistula (high lesion) are common in male infants. +Among the males with high or intermediate lesions, 80% are rectovesical fistulae, but among the females with high defect, 80% have a rectovaginal fistula. There are significant chances of associated anomalies in case of higher anorectal anomalies. +An X-ray film of the abdomen is obtained 12-24 hr after birth, with the baby being kept in an inverted position. A lateral picture of the pelvis should be obtained to define whether the rectal pouch is above or below a line drawn from the pubis to the coccyx. +Treatment is surgical. Prognosis is better with low defects. About 80 to 90% of patients become continents after surgery for low defects. More than two-thirds of patients are incontinent after surgery of high defects. + +Neural Tube Defects +Anencephaly. Anencephaly is due to a defect in the +development of neural axis and is not compatible with life. + +Encephalocele. In encephalocele, the brain and/ or its coverings herniate through a defect in the skull. +Congenital hydrocephalus. Congenital hydropcephalus results from impaired CSP circulation or absorption in basal cisterns. This usually follows intrauterine infections such as toxoplasmosis, rubella, cytomegalovirus and syphilis, but may also be the result of a congenital malformation of the aqueduct, Dandy-Walker syndrome (posterior fossa cyst and a defect of cerebellar verrnis), Arnold-Chiari malformation (displacement of brainstem and cerebellum in the spinal canal) or multiple congenital malformations of the nervous system. +Diagnosis should be suspected if the head is too large or sutures and fontanels are wide open or if the head circumference increases rapidly (more than 1 cm in a fortnight during the first three months). CT or MRI scan should be done to confirm the diagnosis. The type of dilatation of ventricles indicates the site of obstruction. +Isolated aqueductal stenosis has better prognosis. Treatment should be directed at the specific cause if +amenable to therapy and surgical intervention such as +ventriculocaval or ventriculoperioneal shunt. +Myelomeningocele. It presents as membranous protrusion at the lumbosacral region and contains meninges, cerebrospinal fluid, nerve roots and a dysplastic spinal cord. The defect is open and not covered by skin. In contrast, meningocele is covered with skin. There may be no associated neurological deficit, but Arnold-Chiari malformation and congenital hydrocephalus are often associated. Severe motor and sensory deficit are common +and urinary and fecal incontinence are usually present. Meningomyelocele is operated only if there is no paralysis oflower limbs and if there is no bladder/bowel involvement. +Folic acid 4 mg per day should be prescribed to the women in periconceptional period to prevent recurrence. + +Cleft Lip and Cleft Palate +Cleft lip is recognized readily (Fig. 8.55), but a careful inspection of the oral cavity is necessary to identify cleft + + + + + + + + + + + + + + +Fig. 8.55: Unilateral cleft lip and cleft palate +___ _s_s_e_n_t_ia_i_P_e_d_ia_t_ri_ _____________________________ +_ +c +s +E + + +palate. A cleft of the soft palate can be easily missed unless the baby is examined carefully. Ventricular septal defect is a common associated anomaly with cleft palate. +In Pierre-Robin syndrome, cleft palate is associated with retracted jaw (micrognathia) and large tongue, with a tendency for glossoptosis. Feeding is difficult in cases of cleft palate. For the first few days, gavage feeding or spoon-feeding may be done. Bottle feeding may be tried with a soft nipple with rubber flange, which close the cleft and help the baby in sucking. If this is not successful, palatal prosthesis may be used. +Management. Management of cleft palate requires a team effort involving a pediatrician, a plastic surgeon, orthodontist, ENT specialist and speech therapist. Cleft lip is repaired in the neonatal period. Operation for cleft palate is generally deferred until the second year. + +Diaphragmatic Hernia +Diaphragmatic hernia occurs because of failure of closure of the pleuroperitoneal membrane. This allows intestinal loops to ascend to the thorax that compress the developing lung and can result in pulmonary hypoplasia (Fig. 8.56). These babies can present at any time after birth. At birth, a baby may be suspected to have diaphragmatic hernia if there is respiratory distress and a scaphoid abdomen. Bag and mask ventilation should be avoided in these babies. Surgical repair after stabilization is the treatment of choice. + +TRANSPORT OF NEONATES +Transport is an important component of sick newborn care. It requires careful attention to vital parameters, temperature and blood glucose levels as well as coordination with the receiving hospital (Fig. 8.57). + + + + + + + + + + + + + + + + + + +Fig. 8.56: Diaphragmatic hernia: Note multiple air filled cysts in left hemithorax, shift of mediastinum to the right and the absence of outline of the left diaphragm + + +Determine the Indication* to transport the baby to higher health facility +Birth weight <1200 g or gestation <30 week +• +Sickness: severe respiratory distress, shock, severe jaundice, maj� malformations requiring surgery, refractory seizures + +Prepare for transport Baby +Stabilize (temperature, airway, breathing, circulation and blood sugar Secure IV line and give necessary treatment before transfer +Logistics +Counsel the parents and family before transport Communicate with referral facility. Provide a brief note +Arrange supplies, equipment and transport vehicle +.. -�------� + +Care during transport +Monitor frequently (temperature, airway and breathing, circulation, IV canula and infusions +Ensure that the baby receives feeds or fluid +Stop the vehicle, if necessary, to manage problems + +Feedback after transport +Communicate with referral team for condition at arrival and outcome + +* Indications may vary as per the facility + +Fig 8.57: Transport of sick neonates + +If the birth of an at-risk neonate is anticipated, the mother should be transported (in utero transport) to a facility with optimum maternal and neonatal care before delivery (in utero transfer). However, if referral of a neonate is unavoidable, efforts should be made to do the best possible job. +The principles of efficient transport are: +i. Make sure that there is a genuine indication for referral. One should explain the condition and reasons for transport to the family. +ii. Correct hypothermia before transporting, as it may worsen on the way. Stabilize the baby as much as possible. +iii. A precise note should be written providing details of the baby's condition, need for referral and treatment given to the baby. +iv. The mother should be encouraged to accompany the baby. In case she cannot accompany immediately, she should be encouraged to reach the facility at the earliest. +v. A doctor/ nurse/ dai/health worker should accompany the baby, if feasible, to provide care en route. +vi. Take the baby to the nearest referral facility (inform them in advance on phone or otherwise), by the shortest route, using the fastest possible and affordable mode of transport. + +FOLLOWUP OF HIGH RISK NEONATES +Improved perinatal and neonatal care has resulted in improved survival of many sick and small neonates who are atrisk for longterm morbidities such as growth failure, developmental delay and visual/hearing problems. A proper and appropriate followup program would help in +Newborn Infants - + + + +prevention, early detection and appropriate management of these problems, thereby ensuring disability and morbidity free survival. + +Who Needs Followup Care? +Table 8.26 lists the cohort of high risk infants who require followup services. + +Table 8.26: Common newborn conditions requiring high risk followup care +Birth weight <1500 g and/or gestation <32 weeks +Perinatal asphyxia: Apgar score ,;3 at 5 min and/or hypoxic ischemic encephalopathy +Mechanical ventilation for >24 hr +Metabolic problems: Symptomatic hypoglycemia and hypocalcemia Infections: Meningitis and/or culture positive sepsis Hyperbilirubinemia >20 mg/dl or requirement of exchange +transfusion + +When to Followup? +The following should be the followup schedule: • 2 weeks after discharge +• At 6, 10, 14 weeks of postnatal age +• At 3, 6, 9, 12 and 18 months of corrected age and then 6 monthly until at least 5 yr. + +What should be Done at Followup? +i. Assessment of feeding and dietary counseling: Parents should be asked about the infants' diet and offered dietary counseling at each visit. Breastfeeding frequency and adequacy should be assessed. The amount, dilution and mode of feeding should be noted if supplemental feeding is given. It is also important to record the duration of exclusive breastfeeding. If a baby is not gaining adequate weight on exclusive breastfeeding, take care of any illness or maternal problems which may interfere with feeding and milk output. If poor weight gain persists despite all measures to improve breast milk output supple­ mentation can be considered. Complementary feeding should be started at 6 months corrected age. Initially, semisolids should be advised in accordance with the local cultural practices. +ii. Growth monitoring: Growth (including weight, head circumference, mid-arm circumference and length) should be monitored and plotted on an appropriate growth chart at each visit. +iii. Developmental assessment: Assessment of developmental milestones should be done according to the corrected age. The milestones should be assessed in four domains - gross motor, fine motor, language and personal-social. Infants who lag behind in any domain should undergo a formal developmental evaluation by a clinical psychologist using tests such as Developmental Assessment of Indian Infant II (DASII + +II). Age appropriate stimulation should be provided to these babies. +iv. Immunization: Immunization should be ensured according to chronological age. Parents should be offered the option of using additional vaccines such as Hemophilus influenzae B, typhoid, MMR. +v. Ongoing problems: Ongoing morbidities such as diarrhea, pneumonia occur more frequently in these babies and should require appropriate treatment. +vi. Neurological assessment: Muscle tone should be assessed, any asymmetry between the extremities should also be recorded. Any history of seizures or involuntary movements should also be recorded. +vii. Eye evaluation: An ophthalmologist should evaluate the baby for vision, squint, cataract and optic atrophy. Subjective visual assessment can be made from clinical clues as inability to fixate eyes, roving eye movements and nystagmus. Objective visual assessment should be done with the Teller Acuity Card. +viii.Hearing evaluation: High risk infants have higher incidence of moderate to profound hearing loss (2.5-5% versus l %). Since clinical screening is often unreliable, brainstem auditory evoked responses (BAER/BERA) should be performed between 40 weeks PMA and 3 months postnatal age. + +METABOLIC DISORDERS +Hypoglycemia +Hypoglycemia is defined as a blood glucose value of less than 40 mg/ dl (plasma glucose less than 45 mg/ dl). +Screening for hypoglycemia is recommended in high +risk situations (Table 8.27). These babies should be screened for hypoglycemia at 2, 6, 12, 24, 48 and 72 hr after birth with reagent strips (dextrostix). Babies showing blood sugar value of less than 40 mg/dl on reagent strip should be treated for hypoglycemia but should have confirmation of hypoglycemia by a lab test as reagent + +Table 8.27: Common causes of hypoglycemia +Inadequate substrate: Small for gestational age (weight for gestation <3rd percentile), gestation <35 week, birth weight <2000 g +Relative hyperinsulinemia: Infants of diabetic mother, large for date baby (weight for gestation >97th percentile), Rh +isoimmunization. +Sickness: hypothermia, sepsis, asphyxia + +strips have high false positive rates. Appropriate for gestational age babies who are breastfeeding adequately do not require any screening for hypoglycemia. + +Clinical Features +Clinically the hypoglycemia may be asymptomatic or may manifest with a range of clinical features like stupor, tremors, apathy, cyanosis, convulsions, apneic spells, +___ _ss_e___ti_a_P_e_d__i a_t_ri_c_ ________________________________ +l +n +s +_ +E + + +tachypnea, weak and high pitched cry, lethargy, difficulty in feeding, eye rolling, episodes of sweating, sudden pallor, hypothermia and rarely, cardiac arrest. + +Management of Hypoglycemia +Prevention of hypoglycemia. All high risk babies should receive proper breastfeeding counseling and support. Adequacy of breastfeeding should be assessed and small babies not able to suck effectively on the breast, should receive expressed breast milk by alternate methods. +Asymptomatic babies. If the blood sugar is more than 20 mg/ dl in an asymptomatic baby, a trial of oral feeds is given and blood sugar be tested after 30-45 minutes. If repeat blood sugars values are above 40 mg/dl, frequent feeding is ensured with 6 hourly monitoring of blood sugar for 48 hr. However if blood sugar values persists below 40 mg/dl, baby should receive IV glucose infusion. +If the initial blood sugar value is less than 20 mg/ dl, then intravenous glucose infusion is started. +Symptomatic babies: A bolus of 2 ml/kg of 10% dextrose should be given, followed immediately by glucose infusion at an initial rate of 6 mg/kg/min. Blood sugar is checked after 30-45 minutes and then 6 hourly. Repeat hypoglycemic episodes may be treated by increasing the glucose infusion rate by 2 mg/kg/min until a maximum of 12 mg/kg/min. If two or more consecutive values are >50 mg/ dl after 24 hr of parenteral therapy, the infusion can be tapered off at the rate of 2 mg/kg/min every 6 hr, with glucose monitoring. Tapering has to be accompanied by concomitant increase in oral feeds. +Followup and Outcomes +Hypoglycemia has been linked to longterm adverse outcomes. These babies are followed up and assessed at one month corrected age for vision/eye evaluation and at 3, 6, 9, 12 and 18 months corrected age for growth, neurodevelopment and vision and hearing loss. + +Hypocalcemia +Hypocalcemia is defined as total serum calcium level of <7 +mg/dl or ionized calcium level of <4 mg/dl. Hypocalcemia +may be of early onset ( <72 hr) or rarely late onset (>72 hr). +Early onset neonatal hypocalcemia: Commonly seen in preterms less than 32 weeks, infants of diabetic mothers, perinatal asphyxia and maternal hyperparathyroidism. Such babies are at increased risk of hypocalcemia. +Late onset hypocalcemia: Neonates born to mothers with vitamin D deficiency, babies on anticonvulsant therapy or with malabsorption, those on cow milk feeding, or with hypoparathyroidism are at risk of late onset hypocalcemia. +Clinical Presentation +Early onset hypocalcemia is usually asymptomatic unlike the late onset hypocalcemia variety and is diagnosed on + +routine screening. The symptoms when present may be of neuromuscular irritability: myoclonic jerks, jitteriness, exaggerated startle and seizures. They may represent the cardiac involvement like tachycardia, heart failure, prolonged QT interval, decreased contractibility. Apnea, +cyanosis, tachypnea, vomiting and lyngospasm are other +rare symptoms. + +Treatment +Prevention. They should receive 40 mg/kg/ day of ele­ mental calcium (4 ml/kg/ day of 10% calcium gluconate). Infants tolerating oral feeds may receive this calcium orally q 6 hourly. Therapy should be continued for 3 days. + +Asymptomatic hypocalcemia. They should receive 80 mg/kg/ day elemental calcium for 48 hr. This may be tapered to 50% dose for another 24 hr and then discontinued. + +Symptomatic hypocalcemia. They should receive a bolus dose of 2 ml/kg/dose. This should be followed by a continuous IV infusion of 80 mg/kg/day elemental calcium for 48 hr. Calcium infusion should be reduced to 50% of the original dose for the next 24 hr and then discontinued. The infusion may be replaced with oral calcium therapy on the last day. +Bradycardia and arrhythmia are known side effects of bolus IV calcium administration and bolus doses of calcium should be diluted 1:1 with 5% dextrose and given under cardiac monitoring. Skin and subcutaneous tissue necrosis may occur due to extravasation. + +Drug Therapy and Breastfeeding +Though most drugs given to mother get transferred into human milk, the amount is not significant and does not pose any risk to the baby. The clinician should evaluate each medication carefully, examine published data on the drug and advise the mother carefully about the use of medications while breastfeeding. Table 8.28 enlists the maternal medications which may fluence the baby. + +Maternal Medications and Fetal Hazards +The risk by exogenous agents to the fetus is most pronounced during the period of embryogenesis and may result in abortion or congenital malformation (Fig. 8.58). In the late part of pregnancy, these agents only cause organ dysfunction or disturbances of enzyme systems. As a general principle, the use of drugs during pregnancy should be minimized. The benefits of medication to the mother must always be carefully weighed against the risk to the fetus. +Drugs listed in Table 8.29 are known to be or suspected to be teratogenic when given during the first trimester of pregnancy. +Newborn Infants - + + +Table 8.28: Maternal medications that confer high risk to breastfed infants +Amiodarone Accumulation in breast milk may cause thyroid suppression and cardiovascular toxicity Anticancer agents Some agents with short hall-lives may permit breastfeeding with brief interruption Doxepin Sedation and respiratory arrest +Drugs of abuse (cocaine, Should be avoided amphetamines, phencyclidine, +heroin) +Ergotamine, cabergoline, Ergotism has been reported bromocriptine +Sodium or potassium Iodine concentration in milk may cause thyroid suppression in infants iodide; povidone-iodide +solutions +Methotrexate Immune suppression; concentration in gastrointestinal tract of infant +Lithium Lithium concentrations in infant plasma may reach 33-40% of maternal levels Radioisotopes Brief interruptions advised; consult Nuclear Regulatory Commission recommendations Tetracycline Short-term use (up to 3-4 week) are not harmful + + + + + + + + + + + + + + + + +Fig 8.58: Warfarin embryopathy. Maternal warfarin intake during first trimester has resulted in CA) severe hypoplasia of nasal bones requiring tracheostomy for (B) maintenance of upper airways (solid arrow) and epiphyseal stippling (open arrow) + +EFFECT OF MATERNAL CONDITIONS ON FETUS AND NEONATES +Diabetic Mellitus +Diabetes is one of the most common endocrine disorders affecting women during pregnancy. The following complications are likely to occur during pregnancy of a diabetic mother. +i. Fetus may die suddenly during the last trimester of pregnancy +ii. Macrosomia or large size of the body (Fig. 8.59) and its attending risks during delivery such as birth trauma, asphyxia and increased possibilities of cesarean section +iii. Neonatal respiratory distress +iv. Metabolic problems such as hypoglycemia and hypocalcemia +v. Polycythemia, increased viscosity of blood and hyperbilirubinemia + +vi. Higher risk of congenital anomalies. (Infants of mothers with diabetes are 20 times more at risk to develop cardiovascular defects) + +Pathogenesis +Maternal hyperglycemia leads to fetal hyperglycemia and +that in turn leads to fetal hyperinsulinemia (Pederson hypothesis). Insulin is an anabolic hormone and promotes growth. Excess maternal glucose and amino acids provide the substrate for increased synthesis of protein, lipids and glycogen in the fetus. Large fetal size is mostly due to the accumulation of fat. +Hyperinsulinemia in the neonate causes hypoglycemia. The cause of hypocalcemia is not clear but is probably +due to diminished production of parathormone. Hyper­ +bilirubinemia may be due to the increased red cell mass. Since insulin blocks induction of enzyme system, this may explain lower production of surfactant. Reduced surfactant pool and the higher risk of preterm deliveries explains higher risk of respiratory distress syndrome in these babies. + +Management +The infant should be screened for malformations and injuries. Frequent breastfeeding should be encouraged. The neonate should be monitored for blood glucose levels during first three days of life. The other morbidities such as respiratory distress, hyerbilirubinemia should treated appropriately. + +Hypothyroidism +Hypothyroidism during pregnancy if treated adequately does not affect pregnancy outcomes; however, inadequate treatment of the mother predisposes the fetus to adverse neurodevelopment. Neonate should be screened for hypothyroidism using either cord blood or on blood sample taken after 72 hr of birth. +___ _s_s_e_n_ _ial_P_e_d_ iat ics _________________________________ +E +_ +_ +r +_ +_ +t +_ + + + +Drugs or chemical +Alcohol Amphetamines Androgens Barbiturates + +Chloroquine Diazepam Dicumarol + +Diphenylhydantoin Excessive smoking Gentamicin +Heroin Indomethacin Iodides +Lithium carbonate Propylthiouracil Methotrexate +Oral contraceptives Progestins +Qine Radiation Tetracycline Tolbutamide +Vitamin D (heavy dose) + +Table 8.29: Common teratogenic drugs Teratogenic effect +Growth retardation; cardiac, limb and facial anomalies Learning disability, motor incoordination, hepatic calcification +Cleft lip and palate, tracheoesophageal fistula, congenital heart disease, masculinization +Cleft lip and palate, congenital heart disease, induction of hepatic microsomal enzymes, respiratory depression, withdrawal symptoms +Deafness after prolonged use, hemolysis in susceptible individuals Cleft lip and palate, apnea, hypothermia +Bleeding, fetal death, depressed nasal bridge, stippling of phalanges, choanal atresia, cardiac, renal and ophthalmic defects +Facial, cardiac and limb anomalies Growth retardation +Eighth nerve damage +Intrauterine death, low birth weight, sudden infant death Low birth weight, platelet dysfunction +Hypothyroidism, goiter Congenital heart disease, goiter Hypothyroidism +Congenital malformation, fetal death Cardiac, limb and visceral anomalies Masculinization, advanced bone age +Deafness, neurologic anomalies, thrombocytopenia Microcephaly, mental retardation +Staining of teeth, enamel hypoplasia, inhibition of bone growth, congenital cataracts Fetal death, thrombocytopenia +Mental retardation, supravalvular aortic stenosis, ventricular opacities, elfin facies + + + + +should not be separated from the mother. Exclusive breastfeeding is encouraged. The infant should be given isoniazid prophylaxis (5 mg/kg/day) and is evaluated at 6 weeks of age. If there is any evidence of tubercular infection in the baby (clinically or radiologically), the infant should be started on antitubercular therapy. If the infant does not have any evidence of tuberculosis at 6 weeks, the isoniazid therapy continued for 6 months and the infant given BCG vaccine after 2 weeks of cessation of therapy. + + + + + + +Fig. 8.59: Infant of diabetic mother. Note the large size of the baby with broad shoulders and torso and a relatively smaller head + +Tuberculosis +If the mother has active pulmonary tuberculosis that has been treated for less than 2 months before birth or the diagnosis of tuberculosis was made after birth, the baby is at risk to acquire infection from the mother. Such babies + +Syphilis +Syphilis infection can be transmitted to the infant who have significant disease and its sequelae. If the mother was diagnosed to have syphilis and she received adequate treatment at least one month before delivery, the infant does not require any treatment. +If the mother did not receive any treatment or inadequate treatment or her treatment status is not known and the neonate does not have any signs of congenital syphilis, the infant should be treated with procaine or benzathine penicillin. Along with the baby, the mother and her partner should also be treated. +I ----------------------------------N_e_w_b_o_r_n_i_n_fa_ n_ts,.- + + +If the infant shows signs of congenital syphilis, he should be treated with crystalline penicillin for 10 days. +The infant should be followed up in four weeks to examine the baby for growth and signs of congenital syphilis. + +Hepatitis B Infection +The women who have hepatitis B infection (active or carrier stage) can transmit the infection to their babies. Such babies should receive hepatitis B vaccine within 12 hr of birth, which can prevent perinatal transmission of hepatitis B virus significantly. Hepatitis B immuno­ globulins (HBIG; 200 IU, IM) can be given to enhance the protection but it is costly and there are availability issues. + +HIV infection +Most children living with HIV acquire the infection through mother-to-child transmission (MTCT). HIV infec­ tion can be transmitted from an infected mother to her fetus during pregnancy, delivery, or by breastfeeding. +Prevention +In the absence of any intervention, the risk of perinatal transmission is 15-30% in non-breastfeeding populations. Breastfeeding by an infected mother increases the risk by 5-20% to a total of 20-45%. +The risk of MTCT can be reduced to under 2% by interventions that include antiretroviral (ARV) prophyl­ axis given to women during pregnancy and labor and to the infant in the first 6 week of life, obstetrical interventions including elective cesarean delivery (prior to the onset of labor and rupture of membranes) and complete avoidance of breastfeeding. + + +Approach to a women with HIV infection and her infant is summarized in Fig. 8.60. +Breastfeeding +Mothers known to be HIV-infected should only give commercial infant formula milk as replacement feeding when specific conditions are met (referred to earlier as AF ASS-Affordable, Feasible, Acceptable, Sustainable and Safe in the 2006 WHO recommendations on HIV and Infant Feeding) +If replacement feeding is not feasible, mothers known to be HIV-infected (and whose infants are HIV uninfected or of unknown HIV status) should exclusively breastfeed their infants for the first 6 months of life, introducing appropriate complementary foods thereafter and continue breastfeeding for the first 12 months of life. Breastfeeding should then stop once a nutritionally adequate and safe diet without breast milk can be provided. +Immunization +HIV exposed or infected but asymptomatic children should receive all standard vaccines as per national schedule. HIV infected children with immune suppression or symptoms should receive all standard vaccines except BCG, OPV and varicella vaccines. Consider HiB and pneumococcal vaccines in all HIV exposed children (irrespective of symptoms or CD4 count). + +Suggested Reading +Rapid Advice: Use of antiretroviral drugs for treating pregnantwomen and preventing HN infection in infants. World Health Organization,WHO Press, Geneva, 2009; available at www.who .int/ iris/bi tstream/ 1 0665/ 44249/ 1 / +9789241598934_eng.pdf + + + +HIV infected mother (diagnosed by ELISA test) + +Clinical assessment and CD4 count of mother + +ART indicated for mother ART to prevent MTCT + + +Two options +1. Triple ART start at 14 week of gestation until +one week after exposure to breast milk has stopped +2. Antepartum AZT starting at 14 week+ of gestation + intrapartum single dose NVP + AZT + 3TC +l___, ++ postpartum AZT + 3TC for 7 days* + + +Infant +Mother received only AZT for ART +Breastfed: Daily NVP from birth until one wk after all exposure to breast milk has ended +Not breastfed: NVP or AZT for 6 week +Mother received triple drug ART during pregnancy and entire breastfeeding: NVP or AZT for 6 week + +Fig. 8.60: Approach to an infant born to HIV-infected mother. • Efavirenz (EFV) based regimens should not be newly-initiated during the first trimester of pregnancy' single dose nevi rapine (Sd-NVP) and zidovudine (AZT) with lamivudine (3TC) intra- and postpartum can be omitted if mother receives more than 4 weeks of AZT during pregnancy. ART antiretroviral therapy; AZT (4 mg/kg PO per dose twice a day for infant); Sd NVP (10 mg/day for infants <2.5 kg, 15 mg/ day for infants 2.5 kg or more) + +Immunization and +Immunodeficiency + + + + +Aditi Sinha, Surjit Singh + + + + + + + +IMMUNITY +The immune system recognizes microorganisms and other foreign material, discriminates it from self and mounts an appropriate response to eliminate it. There are two major components of immunity: the innate immune sys­ tem and the adaptive immune response. Innate immunity is primitive, nonspecific, has no memory and provides the first line of defense against infections, while the adaptive immune system is highly evolved, specific and has memory, characterized by a rapid rise in immune response when exposed again to the microorganism. + +Innate Immune System +The skin and mucous membranes provide an important mechanical barrier to infection. Gastric acidity is an effective physiologic barrier as very few microorganisms can survive the low acidic pH in stomach. +The complement system consists of multiple serum proteins circulating as inactive precursors. Once triggered, these proteins activate each other sequentially to generate active components. There are three pathways of activation of the complement cascade. The classical complement pathway is triggered by activation of Clq by antibody­ antigen complexes or polyanions (heparin, protamine, nucleic acids from apoptotic cells). The alternative pathway is continuously active at low levels due to spontaneous C3 lysis, and is amplified by binding of complement compo­ nents to pathogen (e.g. bacterial lipopolysaccharides or endotoxin, yeast cell wall). The lectin pathway is activated by binding of mannose binding lectin to mannose residues on pathogen cell surface. Activation of the classical pathway results in low levels of C4, C2 and C3; activation of alternative pathway is characterized by reduced levels of C3 and normal levels of C4 and C2. Activation of C3 by either pathway results in formation of the membrane attack complex, which binds to the surface of bacteria, fungi and viruses leading to their lysis. C3b component can opsonize + +immune complexes or foreign cell surface anaphylatoxin, including C3a, C4a and CSa, bind to receptors on mast cells and basophils, resulting in their de granulation and release of histamine and intracellular enzymes. C3a and CSa induce the adherence of monocytes, macrophage and neu­ trophils to vascular endothelial cells causing extravasation and chemotaxis at the site of inflammation. +Cellular components of innate immunity comprises +polymorphonuclear leukocytes, macrophages and natural +killer (NK) cells. These ingest extracellular material by phagocytosis. The activation of myeloperoxidase in phagolysosomes results in production of superoxide that oxidizes and inactivates microbial proteins. + +Adaptive Immune System +Adaptive immune responses develop through cooperation between lymphocytes and antigen presenting cells following specific antigenic challenge, show tremendous diversity and exhibit immunological memory. The compo­ nents of adaptive immune system are lymphocytes, macrophages and antigen presenting cells. These cells develop and mature in the primary lymphoid organs (bone marrow, thymus) and interact with foreign antigens in secondary lymphoid organs (spleen, lymph nodes, mucosa associated lymphoid tissues, e.g. tonsils and Peyer patches). +Lymphocytes constitute 20-40% of white cells in the peripheral blood and are classified as B cells, T cells and NK cells. T cells are identified by the presence of T cell antigen receptor (TCR), which is associated with CD3 complex to form the TCR-CD3 complex that remains unchanged during cell division. The TCR recognizes antigen only when it is bound to MHC molecules on the surface of antigen presenting cells. Mature T lymphocytes are distinguished into CD4+ cells and CD8+ cells based on the presence of membrane glycoprotein molecules. The normal ratio of the number of CD4+ and CD8+ cells in + + +184 +Immunization and Immunodeficiency - + + + +peripheral blood is 2: 1; this is altered in immunodeficiency and autoimmune diseases. C04+ cells or T helper (Th) cells can recognize antigen only if bound to class II MHC molecules, whereas COB+ cells or T cytotoxic (Tc) cells recognize antigen bound to class I MHC molecules. Th cells differentiate into Thl and Th2 cells under the influence of cytokines. Thl immune response supports inflammation and activates Tc cells and macrophages(e.g. in tuberculoid leprosy, rheumatoid arthritis) whereas Th2 responses induce antibody mediated immunity (e.g. lepromatous leprosy, allergic disorders). Tc cells are important in eliminating intracellular pathogens like viruses, and in organ transplant rejection. +About 5-15% of the circulating lymphocytes are B cells, characterized by surface expression of immunoglobulin isotypes. The majority express IgM and IgO isotypes and less than 10% express IgG, IgA or IgE isotypes. NK cells constitute 15% of circulating lymphocytes and are also present in lymphoid tissues, particularly spleen. They do not carry markers of T or B cells but have IgG Fe surface receptors. NK cells show nonspecific cytotoxicity and enable immune surveillance against viruses and tumors. + +PRIMARY IMMUNODEFICIENCY DISORDERS +A small but significant proportion of children evaluated for frequent infections have immunodeficiency. Immuno­ deficiency disorders can be secondary or primary, the former being far more common. Infection with the human immunodeficiency virus (HIV) is the commonest cause of secondary immunodeficiency (Chapter 10). Table 9.1 lists clinically important causes of secondary immuno­ deficiency. +Primary immunodeficiency disorders can affect any of the major components of the immune system, including T and/ or B lymphocytes, antibody production, phagocyte number or function and complement components. The condition should be suspected in patients presenting with ..2 of the following ten waing signs: (i) ..4 new infections in a year; (ii) ..2 serious sinus infections in a year; (iii) ..2 cases of pneumonia in a year; (iv) ..2 month of antibiotics without effect; (v) failure of an infant to gain weight or grow normally;(vi) recurrent deep skin infections or organ abscesses; (vii) persistent oral thrush, or candidiasis elsewhere beyond infancy; (viii) need for intravenous + +Table: 9 .1 : Common secondary causes of immunodeficiency +Human immunodeficiency virus infection Following measles +Severe malnutrition Nephrotic syndrome +Lymphoreticular malignancies Severe bums +lmmunosuppressive drugs (e.g. glucocorticoids, cyclophos­ phamide, azathioprine) phenytoin +Severe or chronic infections + + +antibiotics to clear infections;(ix) ..2 deep seated infections (e.g. meningitis, cellulitis); and (x) family history of immunodeficiency (based on recommendations of the Jeffrey Modell Foundation). Table 9.2 outlines the investigative workup required in such patients. Conditions that mimic immunodeficiency (gastroesophageal reflux, +Kartagener syndrome) should be excluded. + +Disorders of Specific Immunity +Cellular and/or Combined Immunodeficiency +Severe combined immunodeficiency (SCIO) Child­ ren with the SCIO syndrome usually present in early infancy with severe infections due to viruses, fungi (e.g. Pneumocystis jiroveci) and intracellular pathogens(e.g. Mycobacteria). Tonsillar tissue is usually absent and lymph nodes are not palpable. Left untreated, such babies do not live for more than a few months. The most common form of SCIO is X-linked and caused by mutations in the common gamma chain (IL2 receptor y); approximately one-fourth cases have adenosine deaminase deficiency. SCIO due to purine nucleoside phosphorylase deficiency may present later in childhood with milder immuno­ deficiency. The phenotype in patients with SCIO may be T-B+ NK-(X-linked SCIO), T-B-NK-(adenosine deami­ nase deficiency), T-B- NK+ (mutations in recombination +activating genes) or T- B+ NK+ (IL7Ra deficiency). + +DiGeorge anomaly This disorder arises due to defects in embryogenesis of the third and fourth pharyngeal pouches. It is characterized clinically by an unusual facies (hypertelorism, antimongoloid slant, low set ears, micrognathia, short philtrum of upper lip, bifid uvula), + + +Table: 9.2: Investigations for suspected immunodeficiency Screening investigations +Total and differential leukocyte counts, leukocyte morphology HN serology +X-ray chest +Delayed skin tests (Candida, tetanus toxoid) +Specific investigations +Blood levels of nmunoglobulins: IgG, IgA, IgM; IgG subclasses +Blood group isohemagglutinins (for functional IgM) +Anti-diphtheria and anti-tetanus antibodies (functional IgG) Lymphocyte subsets: CD3, CD4, CD8, CD19, CD16 +Mitogen stimulation tests (response to phytohemagglutinin) Nitroblue tetrazolium (NBT) dye reduction test +CHSO, complement component assays Mannan binding lectin assay +Enzyme assays: adenosine deaminase, purine nucleoside phosphorylase +HLA typing Bacterial killing +Cheiluminiscence studies +- Essential Pediatrics + + + +hypocalcemic tetany, aortic arch anomalies and an absent thymus. In addition, 20-30% patients show a variable T cell defect, ranging from a mildly increased susceptibility to infections to severe disease requiring hematopoietic stem cell transplantation. + +Wiskott-Aldrich syndrome This X-linked recessive disorder is characterized by eczema, thrombocytopenia and recurrent serious bacterial infections. It is caused by mutations at Xpll.22-23, encoding WAS protein present in the cytoplasm of lymphocytes and platelets. The eczema begins in early infancy and may mimic atopic dermatitis with atypical features. Thrombocytopenia is associated with characteristic small sized platelets. Due to impaired responses to polysaccharide antigens, such patients are susceptible to infections with Streptococcus pneumoniae, Haemophilus influenzae and Neisserin meningitidis. The clinical phenotype varies; some children have a fulminant course with repeated severe infections causing death, while others survive childhood and may present predo­ minantly with bleeding manifestations. The risk of lymphoreticular malignancies is increased. There is a profound IgM deficiency in addition to defective T cell signaling which is secondary to the deficient expression of CD43 in lymphocytes. + +Ataxia-telangiectasia This is an autosomal recessive disorder characterized by progressive ataxia (often starting during infancy), telangiectasia (initially on bulbar conjunctiva), sinopulmonary infections, excessive chromo­ somal breakage and increased sensitivity to ionizing radiation. The gene is localized to chromosome 1lq 22-23 and its product regulates the cell cycle. The degree of immunodeficiency is less profound than seen in Wiskott­ Aldrich syndrome. Serum IgA, IgG2 subclass and IgE levels are usually reduced; lymphocyte proliferative res­ ponses are decreased and yo-T cell numbers are increased. + +Hyper lgM syndrome This T cell deficiency result is from a CD40 ligand defect. Affected children have a profound immunodeficiency characterized by low levels of IgG but normal or raised IgM. There is increased susceptibility to infections with P. pneumocystis jiroveci. Some patients may have associated autoimmune disorders. + +Humoral Immunodeficiency +X-linked (Bruton) agammaglobulinemia This was the first primary immunodeficiency disorder to be described. The inheritance is X-linked recessive. Affected boys usually present in the second half of infancy with infections due to pyogenic bacteria. Presentation later in childhood has also been described. Tonsils and lymph nodes are usually atrophic. B cells (CD19+) are absent in peripheral blood but T cells (CD3+) are normal in number and function. The disease is secondary to a mutation in the gene for tyrosine kinase (Btk or Bruton tyrosine kinase). + +Common variable immunodeficiency This term refers to a heterogeneous group of conditions characterized by hypogammaglobulinemia and variable defects in T cell number and function. Presentation is usually much later in childhood and, unlike X-linked agnmaglobulinemia, affected children may have significant lymphadenopathy and hepatosplenomegaly. Unlike X linked agammaglo­ bulinemia, the B cell number is usually normal. Low levels of lymphocyte prollieration following mitogen stimulation may be demonstrated. Mutations in any of the following genes may cause this disorder: inducible costimulator (ICOS), SLAM associated protein (SH2DIA); CD19; CD20; CD81, B cell-activating factor of the tumor necrosis factor family receptor (BAFF-R), tumor necrosis factor receptor superfamily member 13B or transmembrane activator (TNFRSF13B or TACl) or TNFRSF13C. Autoimmune disorders (leukopenia, hemolytic anemia, arthritis) are commonly associated. Patients require close monitoring for development of lymphoreticular malignancies. + +/gA deficiency This is one of the commonest causes of primary immunodeficiency. Affected individuals usually do not have a clinically significant immunodeficiency. They may remain entirely asymptomatic throughout We or have recurrent mild respiratory infections, especially if IgG subclass deficiency is also present. + +/gG subclass deficiency Of the four IgG subclasses, IgGl provides protection against bacterial pathogens (e.g. diphtheria, tetanus), IgG2 protects against capsular polysaccharide antigens (e.g. pneumococcus, Haemophilus influenzae), IgG3 has antiviral properties while IgG4 has antiparasitic activity. Children with deficiency of one of the IgG subclasses may have normal, or sometimes even elevated, total IgG levels. This is ascribed to a compen­ satory overproduction of IgG of other subclasses. + +Transient hypogammaglobulinemia of infancy All infants go through a period of physiological hypognma­ globulinemia between 3-6 months of age, when the trans­ placentally acquired maternal IgG has been catabolized and the child's own immunoglobulin production has not begun. +In some infants, this period of physiological hypogammaglo­ +bulinemia is prolonged to 18-24 months, resulting in the development of transient hypogammaglobulinemia of infancy. Unlike X-linked agammaglobulinemia, the B cell (CD19) numbers are normal. These children recover over time and the longterm prognosis is excellent. The condition must be considered in the differential diagnosis of young children with hypogammaglobulinemia. Serum IgG levels in infancy and early childhood should only be interpreted in the context of age related nomograms. + +Disorders of Nonspecific Immunity Cellular Immunodeficiency +A number of cellular defects have been recognized in the nonspecific arm of the body's immune system. These may +Immunization and Immunodeficiency - + + + +be quantitative (e.g. congenital neutropenia, cyclic neutro­ penia) or qualitative (e.g. chronic granulomatous disease, Chediak-Higashi syndrome). Chronic granulomatous disease refers to a group of disorders with reduced activity of NADPH oxidase leading to impaired generation of superoxide radical. The disease is X-linked in more than 50% patients secondary to mutations in the gene encoding gp9-PHOX, while others have autosomal recessive inheri­ tance with mutations in the gene encoding p47-PHOX on chromosome 7. Children present with recurrent life­ threatening infections, often starting in early infancy. These infections are typically caused by catalase-positive bacteria (e.g. Staphylococcus aureus, Serratia spp.). Fungal infections are also common, especially Aspergillus. Typical findings include persistent pneumonia, prominent lymphadenitis, multiple liver abscesses and osteomyelitis of the small bones of hands and feet. The diagnosis is suggested by screening on nitroblue tetrazolium dye reduction test (NBT), and confirmed by flow cytometric evaluation. +Humoral Immunodeficiency +Individuals with deficiencies of the early complement components (C2-C4) may present with recurrent bacterial infections, while those with deficiency of the later compo­ nents (C5-C9) have predilection for Neisseria infections. Systemic lupus erythematosus may occur in individuals with C2/C4 deficiency. A deficiency of the Cl esterase inhibitor is associated with hereditary angioneurotic edema, characterized by sudden appearance of recurrent nonitchy swellings in the body. + +Miscellaneous +Hyper /gE syndrome This is characterized by recurrent 'cold' staphylococcal abscesses involving the skin, joints and lungs, and markedly elevated serum IgE concen­ trations (usually >2000 IU/ml). Inheritance is variable. +Mannan binding lectin deficiency This is a dominantly inherited, relatively common disorder characterized by recurrent respiratory infections in early childhood. The degree of immunodeficiency is never profound; most patients remain asymptomatic throughout life. +Table 9.3 summarizes the findings in various forms of primary immunodeficiency. + +Treatment of Primary Immunodeficiency Disorders +Hematopoietic stem cell transplantation is the treatment of choice for most forms of significant cellular immuno­ deficiency (e.g. SCID, Wiskott-Aldrich syndrome, hyper IgM syndrome). For it to succeed, the procedure should be done in early infancy. However, it cannot be carried out for children with ataxia-telangiectasia. +Children with X-linked agammaglobulinemia and com­ mon variable immunodeficiency need to be administered 3-4 weekly injections of IV immunoglobulin (IVIG). While expensive, therapy can result in an almost normal lifespan. While children with IgA deficiency usually do not require any specific therapy, those with IgG2 subclass deficiency may require monthly replacement IVIG therapy. Prophy­ lactic therapy with antimicrobials (usually cotrimoxazole) is required for some children with IgGl and IgG3 deficiency. + + +Table 9.3: Clinical clues to the diagnosis of primary immunodeficiency +Type of infection Age at presentation Associated findings Likely etiology + +Pneumonia or diarrhea; crypto­ sporidiosis; disseminated BCG infection + +Pneumonia; pyogenic infections (S. pneumoniae, H. influenzae) + +First few months of life + +-6mo + +Failure to thrive; rash; Severe combined immuno­ atrophic tonsils and deficiency +lymph nodes +Only boys affected; failure X-linked agammaglobulinemia to thrive + + + +Diarrhea, sinopulmonary infections; often pyogenic (S. pneumoniae, H. injluenzae) + +Later childhood (>5-10 yr) + +Hepatosplenomegaly; lymphadenopathy + + +Common variable immunodeficiency + + + +Recurrent staphylococcal cold abscesses, pneumonia (often with pneumatocele +Recurrent or persistent giardiasis +Recurrent staphylococcal infections of lungs, skin or bone; persistent fungal (Aspergillus) pneumonia; liver abscess +Pyogenic bacteria (S. pneumoniae, H. influenzae) +Recurrent Neisseria infections, e.g. meningitis +Recurrent infections + +Recurrent bacterial infections, e.g. pneumonia + +Any age + +Any age +Usually early childhood + +-6 mo + + + +Early infancy + + +Coarse facial features, eczematous rash +Autoimmune diseases +Lymphadenopathy; draining nodes; +hep atosplenomega I y + + + + +Boys; atypical eczema; thrombocytopenia +Progressive ataxia; precedes telangiectasia + + +Hyper IgE syndrome + +IgA deficiency +Chronic granulomatous disease + + +Deficiency in early complement components +Deficiency in late complement (CS-9) components +Wiskott-Aldrich syndrome + +Ataxia-telangiectasia +- Essential Pediatrics + + + +Longterm cotrimoxazole and itraconazole prophylaxis has greatly improved the management of chronic granu­ lomatous disease. Interferon-y, although expensive, has been used for the treatment of life-threatening infections as well as for prophylaxis in difficult cases. Some children with CGD may require bone marrow transplantation. +While there is no specific therapy for complement deficiencies, plasma infusions may be useful in life­ threatening situations. For Cl esterase inhibitor deficiency, prophylactic danazol or stanozolol therapy results in significant improvement. Injections of synthetic Cl esterase inhibitor is required if there is laryngeal involvement with airway compromise. Therapy with adrenaline and hydrocortisone is usually of no benefit. + +Intravenous lmmunoglobulin +Intravenous immunoglobulin (IVIG) is pooled normal intact polyspecific IgG derived from the plasma of healthy donors who have been subjected to strict screening procedures. Each batch of IVIG represents a donor pool of 4000-8000 individuals such that the repertoire of antibodies is representative of the population at large. Most IVIG preparations contain 90% monomeric IgG with only small amounts of IgA and IgM. Ideally, the IgG subclass distribution of IVIG should be the same as in normal plasma, but this depends on the manufacturing process. For instance, some IVIG preparations do not contain adequate quantities of IgG3. +IVIG is the treatment of choice for Kawasaki disease, autoimmune demyelinating polyradiculoneuropathy and idiopathic thrombocytopenic purpura. The dose is 2g/kg given as a single infusion. However, lower doses are equally effective in idiopathic thrombocytopenic purpura. IVIG is also used as replacement therapy in various forms of hypogammaglobulinemia. The recommended dose is 0.4-0.6 g/kg every 3-4 weeks. Its use may also be considered in selected cases of severe myasthenia gravis, autoimmune neutropenia, neonatal alloimmune and auto­ immune thrombocytopenia, lupus crisis, dermatomyositis not responding to conventional steroid therapy and certain vasculitides. IVIG has been used for prophylaxis and treatment of neonatal sepsis in low birthweight babies but the results are equivocal. Use of IVIG for treatment of +sepsis in older children is controversial. +Administration of IVIG is commonly associated with adverse effects. The infusion must be started very slowly (initially a drop per minute) and the child monitored for allergic reactions, including anaphylaxis. The infusion rate should be slowed or discontinued if the child develops chills or rigors. Longterm risks include transmission of hepatitis C infection. The risk of acute renal failure is negligible with current iso-osmolar preparations. +Suggested Reading +Singh S. Primary immunodeficiency disorders -a clinical approach. In: AP! Textbook of Medicine, 9th edn. Eds. Munjal YP, Sharma SK. Jaypee Brothers, New Delhi, 2012;151-4 + + +Singh S, Paramesh H. Immunodeficiency Disorders. In: Indian Acad­ emy of Pediatrics Textbook of Pediatrics, 4th. edn. Eds. Parthasarathy A, Agarwal RI<, Choudhury P, Thacker NC, Ugra D. Jaypee Publish­ ers, New Delhi, 2009;1085-7 +Singh S, Bansal A. Transient hypogammaglobulinemia of infancy: twelve years' experience from Northern India. Ped Asthma All Imm 2005;18:77-81 +Suri D, Singh S, Rawat A, et al. Clinical profile and genetic basis of Wiskott-Aldrich syndrome at Chandigarh, North India. Asian Pac J Allergy Immunol 2012;30:71-8 + +IMMUNIZATIO ----------------- +N +Immunization is the administration of all or part of a pathogen or preformed antibodies to elicit an immuno­ logical response that protects from disease. Considered one of the most cost effective health interventions of all times, immunization programs have enabled the eradication of small pox, elimination of poliomyelitis from several countries and a significant decline in incidences of measles, tetanus and diphtheria. Advances in vaccine technology have led to the introduction of potent vaccines against a wide spectrum of infections. + +Terminology +Active immunity is the protective response mounted by the immune system following exposure to an infectious organism (as clinical or subclinical infection) or after vacci­ nation with live or killed organism, a toxoid or subunit. Active immunity comprises humoral (antibody-mediated) and/or cellular (cell-mediated) immune responses. Following first exposure, the primary immune response is slow to develop (over 3-14 days or longer) and may or may not be sufficient to counteract the infection. The humoral response involves formation of IgM followed by IgG antibodies. Host response to re-exposure to the infectious agent (or its component), termed secondary response, is fairly rapid, involves induction of high titers of IgG anti­ bodies, is usually sufficient to prevent disease and provides protection for several years. + +Passive immunity refers to protection from disease provided by introduction of preformed animal or human antibodies into the body. Examples include the passage of IgG from the mother across the placenta to the fetus, transmission of secretory IgA in breast milk, and adminis­ tration of immunoglobulin or antisera to prevent disease (see section on 'Passive Immunization'). While these antibodies provide immediate protection by neutralizing pathogenic toxins or restricting viral multiplication, the effect is not sustained. +A vaccine is composed of one or more antigens of a pathogenic agent which, when administered to a previously unexposed individual, will elicit an immune response but not cause disease. The secondary immune response, elicited when the host encounters the pathogen itself, is rapid and protects from disease. +Immunization and Immunodeficiency + + + +Immunization is the process of inducing acquired immunity, by administering (i) live killed or attenuated organisms or specific antigens (active immunization), usually prior to natural exposure to infectious agent; or (ii) preformed exogenous antibodies, given soon after or prior to exposure, in order to suppress disease (passive immunization). +Vaccination is to the process of administration of a vaccine. Vaccination may elicit predominantly humoral immune response (e.g. Haemophilus influenza b vaccine), cellular immunity (e.g. BCG), or both responses (e.g. most vaccines). +Seroconversion refers to the change from antibody negative to antibody positive state, due to induction of antibodies in response to infection or vaccination. +Seroprotection refers to the state of protection from disease, due to the presence of detectable serum levels of antibody. +Immunogenicity is the ability of a vaccine to elicit an immune response, whether cellular, humoral or both. +Adjuvants are substances unrelated to the organism that, when added to a vaccine, enhance its immunogenicity. The action results from nonspecific stimulation of lymphocytes or by enabling slow release of the antigen. Examples include aluminum hydroxide and lipids. +Protective eficacy is the vaccine's actual ability to protect against disease. Live viral vaccines and toxoids have good protective efficacy, while BCG and killed bacterial vaccines may not protect from disease. It is assessed in prospective or retrospective epidemiological studies as follows: +Efficacy= (rate of disease in unvaccinated persons-rate of disease +in the vaccinated) x 100/rate of disease in unvaccinated persons +Vaccine effectiveness is the ability of a vaccine to protect the population from disease, when administered in an immunization program. Vaccine effectiveness depends on vaccine efficacy, program implementation and herd effect (see below). +Vaccine failure is the occurrence of disease in an individual despite vaccination. Primary vaccine failure is the inability of the recommended vaccine dose(s) to induce an immune response, while secondary failure refers to the occurrence of disease despite an immune response. Vaccine failure is rare + + +with measles, diphtheria and tetanus vaccines. Primary vaccine failure may occur despite 3 doses of oral poliovirus vaccine (OPV) and secondary failure may be seen after BCG, pertussis and typhoid vaccines. +Herd effect. If a large proportion of susceptible individuals are protected from infection with an organism by simul­ taneous vaccination, the transmission chain of the infectious agent can be broken by reducing carriage of the causative microorganism by vaccinated individuals, thus decreasing the risk of disease even among the unimmu­ nized individuals. This phenomenon, termed the herd effect, is less pronounced for vaccines that protect only against disease (e.g. diphtheria) than those that prevent infection (e.g. measles, OPV). Vaccines with low protective efficacy (e.g. pertussis and typhoid) have insignificant herd effect. There is no herd effect for vaccines against diseases where humans are not the chief reservoir (e.g. tetanus). Herd effect is utilized as one of the strategies for eradication of poliovirus, and potentially, during measles epidemics. Herd immunity refers to the proportion of immune individuals in a population. + +Types of Vaccines +A good vaccine is one that is easy to administer, induces permanent immunity, is free of toxic substances, has minimal side effects and is relatively stable for prolonged time. The timing of administration depends on the age at which the disease is anticipated, the ability to mount immune response to administered antigen(s) and feasi­ bility. Vaccines may consist of live attenuated, killed or inactivated organisms, modified toxins (toxoids), or subunits. Some examples are listed in Table 9.4. + +Live Vaccines +Live vaccines replicate in the host to produce an immune response mimicking natural infection. Therefore, these vaccines actually infect the recipient but do not cause disease because the potency of the organism has been attenuated. However, the vaccine may cause disease in immunocompromised hosts. Rarely, an attenuated viral vaccine may revert to its virulent form causing disease. + + +Table 9.4: Types of vaccines + +Description +Live attenuated organism + +Killed or inactivated organism + +Modified bacterial toxins or toxoids Bacterial capsular polysaccharide +Subunit + + +Bacterial Viral +Bacterial Viral + + +Bacterial Viral + +Example +BCG, oral typhoid (S. typhi Ty21a) +OPV, measles, MMR, varicella, rotavirus, yellow fever +DTwP, whole cell killed typhoid +IPV, rabies, hepatitis A, influenza (whole virion) +Diphtheria toxoid, tetanus toxoid +Salmonella typhi (Vi), Hib, meningococcal, pneumococcal +Acellular pertussis +Recombinant hepatitis B, influenza (split subunit) + +BCG Bacillus Crnette Guerin vaccine; DTwP diphtheria toxoid, tetanus toxoid, whole cell killed pertussis vaccine; Hib Haemophilus influenza +type b; IPV inactivated poliovirus vaccine; MMR measles mumps and rubella vaccine; OPV oral poliovirus vaccine +- Essential Pediatrics + + + +Storage and transportation conditions are critical to maintaining the potency of live vaccines. +Usually a single dose of live vaccines is sufficient to induce immunity; OPV is an exception where multiple doses may be required to infect the intestinal mucosa. +Residual maternal antibody in the infant's serum may neutralize the organism before infection occurs, thus interrupting the 'take' of a vaccine; hence, vaccines like measles and measles, mumps, rubella (MMR) are administered beyond 9 months of age. BCG and OPV are exceptions where maternally derived antibodies do not interfere with vaccine 'take'. This is because BCG induces cell mediated immunity that is not transferred from mother to fetus, and OPV infects the gut mucosa which is not interrupted by residual maternal antibody. + +Killed Vaccines +Killed vaccines, prepared by growing bacteria or viruses in media followed by heat or chemical (e.g. formalin) inactivation, do not cause infection but elicit protective immune response. Interference by maternal antibodies is less significant. However, multiple doses are required since the organism cannot replicate in the vaccinee. The immunity is not permanent; booster doses are necessary to ensure prolonged protection. Most killed bacterial and some killed viral vaccines (e.g. influenza) are associated with significant local and systemic reactions. These vaccines are relatively heat stable. + +Toxoids +Toxoids are modified toxins that, if well purified, are not injurious to the recipient. Primary immunization is in form of multiple divided doses in order to decrease the adverse effects at each administration and to elicit high antibody titres with repeated exposure to the same antigen. Booster doses are required to sustain the protection. + +Subunit Vaccines +Other nonreplicating antigens include capsular poly­ saccharide and viral or bacterial subunits. Capsular poly­ saccharides are carbohydrate antigens that elicit humoral response by stimulating B cells directly, without modulation by helper T cells. Hence, there is no immuno­ logical memory and the antibodies produced are of the IgM class alone, rather than an IgG response. + +Principles of Immunization +While immunizing children, certain guidelines are useful in order to maximize the benefit from vaccination. Important considerations during immunization are as follows: +i. Compliance with the recommended dose and route of vaccination limits adverse events and loss of efficacy. +ii. A minimum interval of 4 weeks is recommended between the administrations of two live vaccines, if + +not administered simultaneously. Exceptions are OPV and MMR and OPV and oral typhoid (Ty21a), where administration of one before or after another is permitted if necessary. +iii. Killed antigens may be administered simultaneously or at any interval between the doses. However, a minimum interval of 4 weeks between doses of DPT enhances immune responses. A gap of 3-4 weeks is recommended between two doses of cholera or yel­ low fever vaccine. +iv. There is no minimum recommended time interval between two types of vaccines. A live and an inacti­ vated viral vaccine can be administered simulta­ neously at two different sites. +v. A delay or lapse in the administration of a vaccine does not require the whole schedule to be repeated; the missed dose can be administered to resume the course at the point it was interrupted. +vi. Mixing of vaccines in the same syringe is not recom­ mended, unless approved by the manufacturer. +vii. The following are not contraindications to immuni­ zation: minor illnesses (e.g. upper respiratory tract infection and diarrhea, mild fever), prematurity, history of allergies, malnutrition, recent exposure to infection and current therapy with antibiotics. +viii. Live vaccines are contraindicated in children with inherited or acquired immunodeficiency and during therapy with immunosuppressive drugs. Live viral vaccines may be given after short courses (less than 2 weeks) of low dose steroids. +ix. Immunoglobulins interfere with the immune response to certain live vaccines like measles or MMR. If immunoglobulins are administered within 14 days of the vaccine, vaccination should be repeated after 3--6 months. Immunoglobulins do not interfere with the immune response to OPV, yellow fever or oral typ­ hoid vaccines. Hepatitis B, tetanus and rabies vaccine or toxoid may be administered concurrently with their corresponding immunoglobulin. +x. Active immunization is recommended following exposure to rabies, measles, varicella, tetanus and hepatitis B. + +COMMONLY USED VACCINES +The following section describes vaccines used commonly, either as a part of the National Immunization Program, or as recommended by the Indian Academy of Pediatrics Committee on Immunization (IAPCOI, 2012) for all children. Some vaccines are recommended for use only in certain high-risk categories of patients. Important instructions for vaccination are summarized in Boxes. + +BCG Vaccine +The Bacillus Calrnette Guerin (BCG) vaccine is a live attenuated vaccine that protects against tuberculosis. The +Immunization and Immunodeficiency - + + + +most common used strains of BCG bacteria are Copen­ hagen (Danish 1331), Pasteur and Glaxo. The Danish 1331 strain used in India was produced at Guindy, Tamil Nadu. The vaccine is available as a lyophilized (freeze dried) powder in a vacuum-sealed dark multidose vial that is reconstituted with sterile normal saline. Each dose contains 0.1-0.4 million live viable bacilli. Since the vaccine is extre­ mely sensitive to heat, the cold chain should be maintained during transit. While the lyophilized form is stable for one year at 2-8°C, the potency drops rapidly upon reconstitution. BCG vaccine primarily induces cell mediated immunity. The protective efficacy of BCG vaccine against severe forms of tuberculosis (e.g. miliary tuberculosis, tubercular meningitis) is about 80%, and the risk of death from tuberculosis is reduced significantly. However, primary infection is not prevented and protection from pulmonary tuberculosis is only 50%. Since childhood tuberculosis accounts for 15-20% of cases, vaccine administration in infancy is useful in preventing serious morbidity. Due to lack of interference in cellular immune response by maternal antibody, administration at birth provides early protection, ensures compliance and is +convenient to implement. +Conventionally, the BCG vaccine is administered on the left shoulder at insertion of the deltoid to allow easy identification of the BCG scar (Box 9.1). Intradermal injection using a 26G needle raises a wheal of about 5 mm. Bacilli multiply to form a small papule by 2-3 weeks that enlarges to 4-8 mm in size at 5-6 weeks. The pa pule ulcerates and heals by scarring at 6-12 weeks. Most children show a positive tuberculin test if tested 4-12 weeks after immunization. Adverse effects including persistent ulce­ ration and ipsilateral axillary or cervical lymphadenopathy are more likely with subcutaneous injection. Children with severe cellular or combined immunodeficiency may develop disseminated BCG disease. Children who are tuberculin positive have an accelerated and enhanced res­ ponse to BCG administration. This BCG test was previously used as a diagnostic test for tuberculosis. Although consi­ dered more sensitive than tuberculin test, the BCG test carries risk of severe ulceration, and is used rarely. + +Box 9.1: Bacillus Calmette Guerin (BCG) vaccine +Dose, route 0.1 ml; intradermal +Site Left upper arm at insertion of deltoid Schedule +National Program At birth; up to 1 yr if missed (catch up) +IAP 2012 As above; catch up till 5 yr +Adverse reactions Local ulceration or discharging sinus; axillary lymphadenitis; disseminated infection, osteomyeltis or scrofuloderma (in immunodeficient recipient) +Contraindication Cellular immunodeficiency; symptomatic HIV +Storage 2-8°C; sensitive to heat and light; discard unused vaccine after 4 hr + +Poliomyelitis Vaccines +Vaccination is an important strategy for preventing paralytic poliomyelitis, caused by poliovirus serotypes 1-3, chiefly in young children. Two types of vaccines are available as trivalent preparations, the live attenuated oral poliovirus vaccine (OPV) developed by Sabin, and the inactivated poliovirus vaccine (IPV), developed by Salk. +Oral Polio Vaccine (OPV) +The OPV contains live polioviruses attenuated by repeated passage and multiplication during culture in Vero cells. Each dose (two drops) contains 105-106 median cell culture infectious doses of each serotype 1, 2 and 3. When administered orally, the vaccine viruses infect the intes­ tinal mucosa and multiply in the mucosa! cells, termed as 'take' of the vaccine. Mucosal immunity in response to this 'infection' protects from paralytic poliomyeltis by reducing the chances of infection when wild-type poliovirus is encountered: the wild virus is excreted for shorter periods and in lower numbers, thus reducing feco­ oral transmission and interrupting wild virus circulation. OPV contains magnesium chloride as a stabilizing agent. The vaccine is stable at 4-8°C for 3-4 months and at -20°C for a year, but its potency drops rapidly with temperature fluctuations. Potency is monitored using the vaccine vial monitor (VVM), a heat sensitive patch dis­ played on the label of the vial. The vaccine should be discarded if the color of the inner square in the VVM is as +dark as, or darker than, the color of the outer circle. +Multiple doses of OPV are essential to ensure take, which may be affected by competition for mucosa! infec­ tion by other enteroviruses, concomitant diarrhea (rapid intestinal transit reduces the time available for mucosa! infection) and interruption in the vaccine cold chain. For these reasons, vaccine take and seroconversion rates are lower in developing countries as compared to developed countries. To decrease the chances of vaccine failure, at least 3 doses should be administered 4-8 weeks apart. For convenience, OPV vaccine is given simultaneous with DTP vaccination at 6, 10 and 14 weeks (Box 9.2). Sero­ conversion rates after 3 doses of OPV are highest for serotype 2 (90%) and lowest for serotype 3 (70%). The administration of a 'zero' dose at birth enhances the rates of seroconversion. Two booster doses are given along with DTP boosters at 15-18 months and at 5 yr. +Breastfeeding and mild diarrhea are not contraindi­ cation for the administration of OPV. However, children with inherited or acquired immunodeficiency and pregnant women should not receive OPV. OPV should be avoided in household contacts of immunodeficient patients, due to the risk of feco-oral transmission of OPV strain. +Children below 5 yr should receive additional doses of OPV during pulse polio immunization (PPI) campaigns on every National Immunization Day (NID) and sub­ +National Immunization Day (sNID). In communities +- Essential Pediatrics + + + +Box 9.2: Oral poliovirus (OPV) vaccine Dose, route Two drops; oral +Schedule +National Program Administer one dose at birth or within 15 days (zero dose); three doses at 6, 10 and 14 weeks (primary) and two doses at 15-18 mo and 5 yr (boosters); give additional doses on NIDs and SIAs; catch up till 5 yr +IAP 2012 In sequential IPV-OPV schedule: OPV given at birth, 6 mo, 9 mo and 5 yr +If +IPV not available or not afforded: Give OPV as in National Program +Adverse reactions Vaccine derived poliovirus; vaccine associated paralytic poliomyeltis +Contraindications Inherited or acquired immunodeficiency; symptomatic HIV +Storage 2-8°C; sensitive to heat; use vaccine vial monitor + + +where poliovirus circulation continues, most adults are immune and only young children are susceptible. Simultaneous administration of OPV to all infants and young children in the community interferes with feco-oral transmission of the circulating wild poliovirus. These interruptions in the circulation of the wild virus are expected to eventually eradicate the wild poliovirus. +OPV is the vaccine of choice for the eradication of polio­ virus in countries where wild poliovirus circulation is continued. However, OPV, particularly the serotype 2, is associated with a risk of the virus regaining its neuro­ virulence to cause vaccine associated paralytic polio­ myelitis (VAPP) in 1 of 1.5 million OPV recipients. Another relatively recent phenomenon has been the occurrence of outbreaks of paralytic poliomyelitis by a virulent strain of poliovirus formed by mutation of OPV, called the circulating vaccine derived poliovirus (cVDPV). The epidemiological and biological characteristics of cVDPV are similar to the wild virus. Hence, cVDPV spreads through the community rapidly to cause outbreaks, particularly in areas with low or declining rated of OPV coverage. At least 13 cases of VPDV have been reported from India since 2009. The activities in the PPI program since 1995-96, and the National Polio Surveillance Project since 1997, have been successful in reducing wild poliovirus circulation in India. Some of these measures included the use of monovalent OPV (mOPV, serotypes 1 and 3) and bivalent OPV (bOPV, lacking serotype 2) during supplementary NIDs and mop-up activities, targeting migrant popu­ lations and high-risk areas through supplementary immunization activities (SIAs), environmental surveillance through sewage sampling, and statewise implementation of the Emergency Preparedness and Response Plan. The last wild polio case (serotype 1) was reported from Howrah in January 2011, and India is no longer considered a polio endemic country. The following strategies are + +proposed by the India Expert Advisory Group on Poliomyelitis to ensure sustained poliovirus eradication from India and to prevent the emergence of cVPDV: (i) sustain standard AFP surveillance; (ii) ensure high rates of routine immunization coverage; (iii) switch from trivalent OPV to bOPV (lacking serotype 2) in 2014; (iv) introduce IPV (booster dose to entire population) in 2013 prior to switch to bOPV to minimize risk of emer­ gence of cVPDV type 2; and (v) conduct two rounds of NIDs using trivalent OPV in 2013 and 2014. + +Inactivated Polio Vaccine (IPV) +IPV is a suspension of formaldehyde killed poliovirus grown in monkey kidney, human diploid or Vero cell culture. The vaccine primarily induces humoral immune response, but pharyngeal and possibly, intestinal mucosal antibodies are also induced. Vaccine potency is measured by its 'D' antigen content. Each dose of currently used enhanced potency IPV (eIPV) vaccines contain 40D, 8D and 32D units of the types 1, 2 and 3 polioviruses, respec­ tively. IPV is highly immunogenic, with seroconversion noted in 90-95% infants administered two doses of IPV 2 months apart beyond 8 weeks of age and in 99% of those given 3 doses 4 weeks apart. Hence, vaccination with 2-3 doses of IPV may be combined with DTP being at 6-10 weeks (Box 9.3). +While the titers of secretory IgA antibodies and extent of herd immunity induced by IPV are lower than with OPV, the efficacy of IPV in preventing poliomyelitis is excellent. IPV administration has the advantage of not causing V APP. Hence, most countries with sustained eradication of circulating wild poliovirus have switched to exclusive use of IPV, following a phase of sequential or combined OPV-IPV usage. The Indian Academy of Pediatrics (IAP) recommends the use of a 'sequential IPV­ OPV schedule' (Box 9.3) which shall enable the implem­ entation of an exclusive IPV schedule in the future. The administration of two doses each of IPV and OPV is seroprotective for over 90% of vaccines. The advantage of administering IPV and OPV in sequence is that the risk of + + +Box 9.3: Inactivated poliovirus (IPV) vaccine +Dose, route 0.5 ml; intramuscular or subcutaneous +Schedule +National Program Not recommended +IAP 2012 Sequential IPV-OPV schedule: Administer 3 doses of IPV at 6, 10 and 14 weeks or 2 doses at 8 and 16 weeks (primary) and one dose at 15-18 mo (booster); also give OPV at birth, 6 mo, 9 mo and 5 yr, and on NIDs and SIAs +Catch up Up to 5 yr; 3 doses at 0, 2 and 6 mo Adverse reactions Local pain, swelling Contraindication Known allergy +Storage 2-8°C; sensitive to light +Immunization and Immunodeficiency - + + + +OPV induced V APP is minimized by prior administration of IPV, while ensuring that adequate mucosal immunity interrupts wild poliovirus circulation. Thus, the sequential schedule maintains high rates of mucosal immunity while preventing VAPP. An 'all IPV' schedule would keep the child at a small risk for VAPP through exposure to the OPV virus through contacts or environment before sero­ protective titres are reached by IPV, and is not recom­ mended at present. The IAP schedule retains the birth dose of OPV; this neonatal dose is considered necessary in areas with continued risk of wild poliovirus transmission, and is unlikely to cause V APP in presence of maternally transmitted antibodies. The IAP recommends the administration of OPV on all NIDs and during SIAs. +A child less than 5-yr-old who has completed primary immunization with OPV may be offered IPV as catch up vaccination in three doses (Box 9.3). IPV is the vaccine of choice in patients with immunodeficiency including symptomatic HN, and in siblings and close contacts of such patients. These children should not receive OPV, and should receive an additional booster dose of IPV at 5 yr. + +Diphtheria Vaccine +Diphtheria continues to be a significant cause of childhood morbidity in countries with poor immunization coverage. Natural immunity to diphtheria is acquired through apparent or inapparent infections (see Chapter 10). In developed countries where EPI coverage is high and natural boosting is low, a large proportion of adults are susceptible to diphtheria as a result of waning immunity. Diphtheria vaccine is a toxoid (DT), containing diphtheria toxin inactivated by formalin and adsorbed on aluminum hydroxide that acts as an adjuvant. The quantity of toxoid contained in a vaccine is expressed as its limit of flocculation (Lf) content. The most commonly used vaccine containing DT is DTwP, a combination vaccine containing 20-30 Lf of DT, 5-25 Lf of tetanus toxoid (TT) and >4 IU of whole cell killed pertussis. Com­ mon adverse effects, relating chiefly to the pertussis component, include fever, local pain and induration; +rarely, incessant crying and encephalopathy are seen. Maternal antibodies protect the infant against disease +and interfere with immune responses to DTP vaccination, particularly against pertussis. To ensure protection against diphtheria, vaccination should begin within a few weeks after birth and requires multiple doses. Primary immuni­ zation with 3 doses given 4-8 weeks apart induces satisfactory antitoxin response to DT and TT in 95-100% infants. However, the protective efficacy against pertussis is lower, at about 70-90%. Immunization does not elimi­ nate Corynebacteriurn diphtheriae from the skin or nasopharynx. Booster doses of diphtheria toxoid are required to achieve a protective antibody titer of 0.1 IU / ml and protect against disease in the first decade of life. Hence, a minimum of 5 doses is recommended; three in infancy (primary immunization) and two booster doses. + +Box 9.4 indicates the schedule for administration of DTwP or DTaP, containing OT, TT and acellular pertussis. +Other vaccines containing diphtheria toxoid are diphtheria and tetanus toxoids (DT) and combinations with reduced toxoid content (Td, TdaP). If given beyond 7 yr of age, primary immunization or booster doses should be in the form of Td or TdaP, which contain smaller amounts of diphtheria toxoid (2 Lf) and acellular pertussis vaccine than DTP. This reduction of diphtheria toxoid potency minimizes reactogenicity at the injection site but is sufficient to provoke an antibody response in older children and adults. To promote immunity against diphtheria, Td, rather than tetanus toxoid alone, should be used when tetanus prophylaxis is needed following injuries. In nonendemic countries, revaccination against diphtheria every 10 yr may be necessary to sustain immunity among adults, particularly health-care workers. + +Pertussis Vaccine +Pertussis (whooping cough) is an important global cause of infectious morbidity, with an estimated annual occur­ rence of 16 million cases, chiefly in developing countries. While the incidence of pertussis has declined dramatically following EPI coverage, the infection continues to be endemic even in countries with high vaccination rates. The disease usually affects infants and unimmunized adole­ scents; those <6-month-old have the highest case fatality rate. Natural infections and immunization induce immunity lasting 4-12 yr. +Pertussis vaccine has been traditionally available as DTwP as described above. Two types of pertussis vaccines are available: whole-cell (wP) vaccines based on killed B. + +Box 9.4: Diphtheria toxoid, tetanus toxoid and killed whole­ cell pertussis (DTwP) or acellular pertussis (DTaP) vaccine +Dose, route 0.5 ml; intramuscular +Site Anterolateral aspect of mid-thigh (avoid gluteal region: risk of sciatic nerve injury; inadequate response) +Schedule +National Program DTwP at 6, 10 and 14 weeks (primary); at 15-18 mo and 5, 10, 16 yr (boosters) +IAP 2012 DTaP or DTwP; primary schedule as above; Tdap/Td at 10-12 yr; Td every 10 yr +Catch up ,.7 yr: DTaP or DTwP at 0, 1 and 6 mo Catch up >7 yr: Tdap at O mo; Td at 1 and 6 mo +Adverse reactions Local pain, swelling, fever (DTwP>DTaP) Contraindications: (i) Progressive neurological disease (administer DT or dT instead); (ii) anaphylaxis after previous dose; (iii) encephalopathy within 7 days of previous dose Precautions: Previous dose associated with (i) fever >40.5°C within 48 hr; (ii) collapse (hypotonic-hyporesponsive episode) within 48 hr; (iii) persistent inconsolable crying for >3 hr within 48 hr; (iv) seizures within 72 hr +Storage 2-8°C; sensitive to light +-�E ss_e_n_ ti_ a_l_P_e_d_ i_a _tr_ic_ _________________________________ +s +- + + +pertussis organisms, and acellular (aP) vaccines based on highly purified, selected components of the agent. The protective efficacy of primary immunization with 3 doses of pertussis vaccine is only 70-90% and wanes over 6-12 yr, making booster doses essential for continued protec­ tion. The administration of DTwP vaccine is commonly associated with local (pain and redness) and systemic (fever) reactions that are chiefly attributed to the pertussis component (Box 9.4). The incidence of these adverse effects increases with the number of doses administered; hence the vaccine is not used beyond 5 doses or beyond 7 yr of age. DTP is also incriminated in the rare induction of serious neurological complications, though conclusive evi­ dence is lacking. Hence, the vaccine is relatively contra­ indicated in children with progressive neurological disease, but children with stable neurological diseases (e.g. developmental delay, cerebral palsy and idiopathic epilepsy) may be vaccinated. Absolute contraindications to the administration of the vaccine and additional adverse events that require precaution are listed in Box 9.4. Parents should be cautioned about the risk of recurrence of events listed in 'precautions' with further doses of the vaccine; if such an event recurs with a subsequent dose, further doses are contraindicated. Individuals in which DTP is contra­ indicated should complete the immunization schedule with DT, that contains the same doses of DT and TT as DTP, but is devoid of the pertussis component. DT is recommended for use up to the age of 7 yr, beyond which Td must be used. + +Acellular Pertussis Vaccine (DTaP) +The suspicion that the active pertussis toxin and endotoxin are responsible for the high incidence of adverse events associated with DTwP administration led to the development of various types of purified acellular pertusssis vaccines, or DTaP. The available DTaP vaccines contain inactivated pertussis toxin (PT) and one or more additional pertussis antigens, like filamentous hem­ agglutinin (FHA), pertactin, fimbrial protein and a nonfimbrial protein. Trials have demonstrated that the efficacy of these vaccines is similar to DTwP, but the risk of systemic and local side effects is reduced significantly. Each dose of the vaccine contains at least 4 IU (10-25 mg) of PT component and 6.7-25 Lf of DT. +The DTaP vaccine is not recommended as part of the National Program in India due to its cost. However, the IAP recommends that the vaccine be offered to children when parents opt for it in view of the advantage of fewer side effects, or are reluctant to the administration of further doses of DTwP after an adverse effect with a previous dose, +while endorsing the continued use of the DTwP in the National Program. It must be noted that the contra­ indication for DTaP are the same as for DTwP; and the +vaccine should not be administered if a previous dose of DTwP or DTaP was associated with immediate +anaphylaxis, or the development of encephalopathy within + +7 days of vaccination. These children should complete immunization with DT instead of DTwP or DTaP. + +Reduced Antigen Acel/ular Pertussis Vaccine (Tdap) and Reduced Antigen Diphtheria Toxoid Vaccine (Td) +Immunity against pertussis induced by natural infection or through immunization in infancy wanes by adole­ scence, resulting in a second peak of the disease in adole­ scence. Pertussis control is unlikely to be achieved if adole­ scents and adults remain susceptible to the disease, because they act as a source of infection to susceptible individuals. Immunity against diphtheria also wanes with time and the only effective way to control the disease is through immunization throughout life to provide constant protective antitoxin levels. +The availability of Tdap offers the prospect of reducing pertussis incidence in the community. The rationale for its use is that the reduced antigen content causes less severe adverse effects while being sufficient to induce protective response in a previously immunized individual (booster effect). The available Tdap vaccines in India contain 5 Lf of tetanus toxoid, 2 Lf of diphtheria toxoid and three acellular pertussis components namely, pertussis toxoid 8 µg, filamentous hemagglutinin 8 µg and pertactin 2.5 µg. Contraindications to Tdap are the same as those listed for DTaP or DTwP. Unimmunized individuals should receive one dose of Tdap if older than 7 years; this is followed by two doses of Td vaccine at 1 and 6 months. In some countries, a single dose of Tdap is administered to all children at 10-12 years, followed by Td boosters every 10 yr. There is no data at present to support repeat doses of Tdap. Tdap may also be used as replacement for Td/ tetanus toxoid (TT) booster in children above 10 yr and adults of any age if they have not received Tdap in the +past and 5 yr have elapsed since the receipt of previous TT/Td vaccine. If less than 5 yr have elapsed since Tdap administration, TT is not required for wound prophylaxis. +The IAPCOI recommends the use of Tdap or DTwP and not Tdap, as second booster in children below 7 yr of age. While standard dose DT is recommended for primary immunization against diphtheria because of its superior immunogenicity and minimal reactogenicity, the reacto­ genicity of the vaccine increases with age. Since the adult preparation Td, containing 5 Lf of tetanus toxoid and 2 Lf of diphtheria toxoid, is adequately immunogenic in adults, it is recommended for booster doses administered to individuals 7 yr of age or older. The vaccine may be used +whenever TT is indicated in children above 7 yr of age. + +Tetanus Vaccine +Extensive routine immunization of pregnant women with two doses of TT has led to a decline in the incidence of neonatal tetanus, previously an important cause of neonatal mortality. Immunizing pregnant women with +two doses, with the second dose administered at least 2 +Immunization and Immunodeficiency - + + + +weeks prior to delivery, provides passive immunity to the baby due to the transplacental passage of IgG antibodies. Tetanus toxin is inactivated by formalin to make tetanus toxoid (TT) and adsorbed onto aluminum salts to enhance +its immunogenicity. Each dose of TT vaccine contains 5 Lf of the toxoid. The vaccine is heat stable and remains potent for a few weeks even at 37°C. The efficacy of TT +vaccine varies between 80-100%. An antitoxin level of 0.01 JU/ ml is considered protective; however, the level of protection available also depends on the toxin load. +Since tetanus may occur at any age, primary immuni­ zation should begin in early infancy. Tetanus toxoid is administered with DT and pertussis (killed or acellular) vaccine in DTP, with 3 doses of the vaccine given 4 weeks apart, followed by boosters at 18 months and 5 yr. DT Td and TT are also available for use in booster immunization at 10 and 16 yr of age and for wound prophylaxis. Previously rnunized school children should receive 2 doses of TT 1 month apart. Recommendations for routine tetanus prophylaxis in wound management and indications of tetanus immunoglobulin (TIG) are listed in Table 9 .5. TT should not be administered after every injury if immunization is complete and last dose was received within last 10 yr. + +Table 9.5: Tetanus prophylaxis following wound +Past doses of IT Clean minor wound All other wounds +TI TIG* TI TIG* Unknown or +<3 doses Yes No Yes Yes �3 doses No•• No No••• No +Use DTwP or DTaP if <7-yr-old and Td or TT in an older child TIG: Tetanus immunoglobulin (250 IU intramuscular) +•• Yes if> 10 yr since last dose Yes if 5 yr since last dose + + +Measles Vaccine +Measles vaccine is a live attenuated vaccine. The strain used in India is derived from the Edmonston Zagreb strain of vaccine virus grown in human diploid cell culture. Measles vaccine has a shelf life of 1 yr at 4-8°C, and loses potency rapidly after reconstitution. The vaccine should +be reconstituted using sterile precautions and any unused vaccine should be discarded after 4-6 hr since bacterial contamination may lead to staphylococcal sepsis and toxic +shock syndrome. Box 9.5 lists standard instructions for its administration. +Maternal immunity may interfere with the immune response to the vaccine during infancy. Administration of the vaccine at 9 months in endemic countries like India balances the need of early protection with the ability to ensure seroconversion. Adequate titers of antibody are generated in 85-90% at 9 months age. In case of an +outbreak, vaccine administration as early as 6 months of + + +Box 9.5: Measles Vaccine +Dose, route 0.5 ml; subcutaneous +Site Right upper arm (at insertion of deltoid) or anterolateral thigh +Schedule +National Program At 9 mo (�6 mo during outbreaks; revaccinate �4 weeks later, preferably at +12-15 mo as MMR) +IAP 2012 At 9 mo; administer at least 2 doses of measles containing vaccine �4 weeks apart; preferably as MMR at 12-15 mo and4-6 yr +Catch up <12 mo: Administer measles vaccine Catch up �12 mo: Administer MMR vaccine +Adverse reactions Fever, transient macular rash ('measles like' illness) 5-10 days later +Contraindications (i) Immunosuppressive therapy (e.g. +alkylating agents, high dose corticoste­ roids); (ii) malignancy; (iii) severe immunodeficiency (e.g. advanced HN); (iv) untreated tuberculosis +Storage 2-8°C; sensitive to heat and light; use within 4-6 hrs of reconstitution + + +age may be carried out, with a repeat dose at 12-15 months as part of measles or MMR vaccine. +Post exposure prophylaxis with immunoglobulin is indicated for all immunocompromised contacts irres­ +pective of immunization status, and exposed infants aged 6-12 months (see section on Passive Immunization). +Unimmunized immunocompetent contacts older than 12 +months should receive measles or MMR vaccine within 72 hr of exposure. + +Measles Mumps Rubella Vaccine +Most developed countries use a combination of measles, mumps and rubella vaccines rather than measles vaccine alone for primary immunization. Since the occurrence of mumps in adulthood is associated with the risk of oopho­ ritis, some programs recommend the administration of mumps vaccine to all young adults who have not had the disease. Rubella vaccination is mainly directed at preven­ tion of the congenital rubella syndrome and not prevention of primary rubella infection, which is a benign illness. +The mumps component of MMR vaccine has live attenuated mumps virus derived from the Jeryl Lynn strain grown in chick embryo or human diploid cell cultures. Clinical efficacy is 75-90%. The vaccine is safe; there is no association of the vaccine with autism or Crohn disease unlike postulated previously. Aseptic meningitis may occur in 1 in 104 to 105 doses, but is mild and often subclinical. Monovalent mumps vaccine is currently not available in India. Available rubella vaccines are derived from the RA 27/3 strain of the virus grown in human diploid or chick embryo cell culture. The vaccine has a seroconversion rate +of over 95% and long lasting immunity, possibly lifelong. +_ E_s_s_e_n_ t_ia_l_P_e_d_ ia_ t_ r-ic_ _______________________________ _ +s +_ + + +Adverse effects following immunization are mild (Box 9.6). The vaccine is contraindicated in pregnant women and in immunocompromised persons. However, MMR vaccine is recommended for asymptomatic and symptomatic individuals with HIV if not severely immunocompromised. Each 0.5 ml dose of the vaccine contains 1000, 5000 and 1000 TCID50 of measles, mumps and rubella, respectively. The vaccine is dispensed as a lyophilized preparation in single and multiple dose. The vaccine should be used within 4 hr of reconstitution to prevent loss of potency. Box 9.6 summarises instructions for its administration. The vaccine is recommended for use beyond 12-15 months of age because maternal antibodies interfere with response to the vaccine if given earlier. IAP recommends two doses of MMR vaccine, to decrease the risk of primary vaccine +failure to the mumps and rubella components. +Haphazard use of rubella or MMR vaccine in children without ensuring optimal immunization coverage may result in an epidemiological shift of disease with more clinical cases in adulthood and a paradoxical increase in congenital rubella syndrome. Hence, the vaccine should be introduced in the National Program only after ensuring that the routine immunization coverage is at least 80%. + +Hepatitis B Vaccine +India has intermediate endemicity for hepatitis B virus (HBV), with about 4% individuals being chronic carriers of the virus. HBV is the leading known cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma. Infection with HBV may be acquired by the perinatal route (vertical transmission), during childhood through close contact with infected family members (horizontal transmission), through transfusions or use of infected needles and by sexual contact. Infection at younger age is associated with + +Box 9.6: Measles, mumps, rubella (MMR) vaccine +Dose, route 0.5 ml; subcutaneous +Site Right upper arm (at insertion of deltoid) +or anterolateral thigh Schedule +National Program At 15-18 mo (only in some states) +IAP 2012 Two doses at 15 (12-18) mo and 4-6 yr; +minimum age 12 mo; second dose may be given at <4 yr but 24 weeks after the +first dose +Catch up 212 mo: Administer 2 doses 24 weeks apart; one +dose if received MMR vaccine previously Adverse reactions Fever, transient rash, arthralgia, aseptic +meningitis, lymphadenopathy +Contraindications (i) Immunosuppressive therapy (e.g. +alkylating agents, high dose corticoste­ roids); (ii) malignancy; (iii) severe +immunodeficiency (e.g. advanced HN); (iv) untreated tuberculosis +Storage 2-8°C; sensitive to heat and light; use +within 4-6 hr of reconstitution + +higher risk of chronic carriage and chronic liver disease. In regions of high and intermediate endemicity, vertical and horizontal transmissions are major modes of infection. Hence the WHO recommends universal hepatitis B vaccination in these regions. The Government of India has initiated the incorporation of the vaccine in the National Immunization Schedule in a phased manner. +The current hepatitis B vaccine is a highly purified vaccine produced by recombinant DNA techniques in yeast species and contains aluminium salts as adjuvant. Each pediatric dose of 0.5 ml contains 10 µg of antigenic component. It is recommended that the dose be doubled in adults, patients on hemodialysis, immunocompromised individuals and those with malignancies. Seroconversion rates are> 95% after three doses. An antibody titre of> 10 mIU/ml is considered protective. Box 9.7 summarizes recommendations for administration of hepatitis B vaccine. Since immunization at birth prevents horizontal trans­ mission, vaccination should begin at birth if the mother's HBsAg status is not known. Immunization at birth, 1 and 6 months is considered ideal in terms of its proven immunological efficacy. Attempts at integrating the vaccination into the National Schedule without increasing number of contacts have led to trials of other schedules which have been found to provide good efficacy. Where birth dose has been missed, it may be given at 6, 10 and 14 weeks of age. Currently, there is no evidence to suggest that booster doses are required. +Hepatitis B surface antigen (HBsAg) screening should be offered to all pregnant women. If the mother is known to be HBsAg negative, vaccination of the child may begin at 6 weeks. Where the mother's status is not known, it is safer to vaccinate the newborn within a few hours of birth. If the mother is known to be HBsAg positive, the child + +Box 9. 7: Hepatitis B vaccine +Dose, route 0.5 ml (1 ml in adults and in children +receiving hemodialysis); intramuscular +Site Anterolateral thigh (deltoid in adults); avoid gluteal region +Schedule +National Program At birth (<12-hr-old), 6 weeks, 14 weeks +IAP 2012 At birth, 6 weeks and 6 mo; may give +3-4 doses in an alternative schedule* +while ensuring that (i) doses 1 and 2 are 24 weeks apart; (ii) doses 2 and 3 are 28 weeks apart; (iii) final dose is at 26 mo +of age and 216 weeks beyond first dose +Catch up Complete 3 doses series; second dose is +given 24 weeks and third dose 28 weeks +after previous dose +Adverse reactions Local soreness; fever; fatigue Contraindication Anaphylaxis after previous dose Storage 2-8°C; do not freeze +*Alternative schedules: (i) birth, 1 and 6 mo; (ii) birth, 6 and 14 weeks; (iii) birth, 6, 10 and 14 weeks; (iv) 6, 10 and 14 weeks +Immunization and Immunodeficiency - + + + +must receive the vaccine within a few hours of birth, along with hepatitis B immunoglobulin (HBIG) within 24 hr of birth at a separate site (see section on Passive Immuni­ zation) If HBIG has been administered, any of the schedules incorporating a birth dose of the vaccine can be used. If HBIG is not administered, the baby should be immunized in an accelerated schedule at 0, 1 and 2 months, along with an additional dose at 9-12 months. +HBIG provides immediate passive immunity and is used in circumstances where an acute exposure to HBsAg positive biological material has occurred. Combined passive and active immunization with concurrent use of HBIG and HB vaccination results in 90% decrease in risk of HBV transmission in circumstances such as needle stick injuries, sexual exposure or use of blood product not screened for HBV (see section on Passive Immunization). + +Varicella Vaccine +Chickenpox (varicella) chiefly affects children and young adults in whom it is usually a benign and self limiting infection. The disease may be associated with compli­ cations when occurring in adults, pregnant women and immunocompromised individuals. The available vaccines are live attenuated vaccines derived from the Oka strain of the virus grown in human diploid cell culture. Each dose of the lyophilized vaccine contains at least 1000 plaque forming units of the attenuated virus. The vaccine elicits both cellular and humoral immune responses and has high (95-99%) protective efficacy. In children above 12 yr, seroconversion rates are 80% with one dose and 90% after two doses. While one dose of the vaccine is sufficient to seroconvert 95% of younger children, two doses are recommended to reduce the risk of breakthrough infections due to waning immunity. +Varicella vaccine is not included in the National Immunization Program since varicella has less public health relevance than other vaccine preventable diseases, the vaccine is expensive, and ensuring high rates of immunization coverage would be essential to ensure that the disease epidemiology does not shift to affect older individuals, causing severe disease. The IAP recommends the use of varicella vaccine in all children where it is afforded (Box 9.8). It is particularly important to vaccinate children with chronic cardiac or pulmonary disease, HIV infection (while CD4 count is >15% for age), leukemia (during disease is remission with chemotherapy discontinued for >3 months) and conditions like nephrotic syndrome where prolonged immunosuppression is anticipated. The vaccine should also be considered in household contacts of immunocompromised children, and in adolescents and adults without history of varicella in the past, particularly if staying or working in an institu­ tional setting (e.g. school, hospital or military establish­ ment). Unimmunized household contacts of patients with varicella should receive varicella vaccine within 72 hr but its protective efficacy is uncertain. Varicella zoster + + +Box 9.8: Varicella vaccine +Dose, route 0.5 ml subcutaneously +Site Anterolateral thigh or upper arm Schedule +National Program Not included +IAP 2012 Two doses at 15--18 mo (minimum age 12 mo)* and 4-6 yr; second dose may be given >3 mo after the first dose +Catch up Complete two dose series with minimum interval of 3 mo between the doses (�4 weeks if �12-yr-old) +Adverse reactions Fever, rash, local pain or redness Contraindications Anaphylaxis after previous dose; lympho­ +penia; immunodeficiency; dring immuno­ suppressive therapy +Storage 2-8°C; protect from light; use within 30 min of reconstitution +*Risk of breakthrough infections is lower if given at 6-month-old, induced antibodies against the cell wall somatic (0) and flagellar (H) antigens. The vaccine had a protective efficacy of 50-70% but required revaccination every 2-3 yr. The serological response interfered with the interpretation of Widal test. Adverse effects were common, including fever, local pain and malaise. This vaccine is currently not available in India. +The Vi capsular polysaccharide vaccine contains the purified Vi antigen that prevents phagocytosis of S. typhi and inhibits serum bactericidal action. This unconjugated polysaccharide vaccine elicits anti-Vi antibodies in children above 2 yr and has protective efficacy of 50-75% after 2 weeks of administration. Each dose of the vaccine has 25 µg of the antigen. The IAPCOI recommends its use in all children every 3 yr beginning at 2 yr (Box 9.9). While a Vi polysaccharide conjugate vaccine has been developed, +_ E_s_s_e_n_ t_ia_i_P_e_d_ i_a _tr_ic_s _________________________________ +_ + + +Box 9.9: Typhoid Vi capsular polysaccharide vaccine +Dose, route 0.5 ml, subcutaneous or intramuscular Site Anterolateral thigh (deltoid in adults) Schedule +National Program Not included +IAP 2012 One dose at 2 yr; repeat every 3 yr Catch up One dose beyond 2 yr +Adverse reactions Local pain, swelling, redness; fever Contraindication Anaphylaxis after previous dose Storage 2-8°C; do not freeze + \ No newline at end of file