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E. Hamid. University of Idaho.

Diagnosis: Careful inspection of skin over the thorax is essential when evaluating chest pain as it may reveal skin lesions causing the pain buy levitra 10mg mastercard. Presentation: Pericarditis presents with a sharp order levitra 10mg, stabbing pain that improves when the patient sits up and leans forward buy levitra 10mg. The child is usually febrile, in respiratory distress, and has a friction rub heard through auscultation. Distant heart sounds, neck vein distention and pulsus paradoxus can occur when fluid accumulates rap- idly. However, it should be noted that chest pain typically resolves when pericardial fluid accumu- lates as it serves to separate the two pericardial surfaces and prevent their friction which is the cause of pericardial pain. Diagnosis: History and physical examination is helpful in making the presumptive diagnosis. Echocardiography is important to assess extent of fluid accumulation and need for intervention to pre- vent cardiac tamponade. Nonsteroidal anti-inflammatory agents are typically used to reduce inflammation and to assist with pain. Steroids may be indicated if fluid accumulation is significant and there is urgent need to reverse inflammatory process. Pericardiocentesis is indicated if pericardial fluid accumulation is excessive and interfering with cardiac output. Cardiac Conditions An essential goal for evaluating any child with chest pain is to rule out cardiac anomalies. Cardiac cause of chest pain is rare; however, it is primary concern of families of children with chest pain and if left undiagnosed may lead to significant complications. The role of any primary care physician confronted with a child with chest pain is to develop a list of differential diagnosis based upon history of illness, family history and physical findings on examination. In making the determination whether the cardiovascular system is the cause of chest pain it is helpful to identify on one hand red flags pointing towards cardiac disease and on the other hand signs which indicate etiologies of chest pain other than the cardiovascular system. Features suggesting cardiac disease (red flags) Abnormal findings in history Syncope Palpitations 418 I. Severe pulmonary or aortic valve stenosis: This can lead to ischemia and results from increase myocardial oxygen demand from tachycardia and increase pressure work by the ventricle. These disorders almost always are diagnosed before the child presents with pain, and the associated murmurs are found on physical examination. Chest X-ray may show a prominent ascending aorta or pulmonary artery trunk, echocardiogram is the key in the diagnosis. Anomalous coronary arteries: Such as anomalous origin of the left or right coronary arteries, coronary artery fistula, coronary aneurysm/ stenosis secondary to Kawasaki disease. These can result in myocardial infarction without evidence of underlying pathology. However, chest pain is not typical in any of these conditions in the pedi- atric cage group. These conditions are associated with significant murmurs such as pansystolic, continuous or mitral regurgitation murmur or gallop rhythm that sug- gests myocardial dysfunction. These patients should be referred for evaluation by a pediatric cardiologist for assessment and treatment. Hypertrophic obstructive cardiomyopathy: This hereditary lesion has an auto- somal dominant pattern and patients have positive family history of the same disorder or a history of sudden death. Children with this disorder have a harsh systolic ejection murmur that is exaggerated with standing up or performing Valsalva maneuver. Echocardiogram is the study of choice to evaluate this condi- tion, referral to a pediatric cardiologist should be done to evaluate patient and his/ her family. Case Scenarios Case 1 History: A 14-year-old girl previously healthy comes to your office complaining of chest pain that started 6 months ago. Pain lasts for few seconds, sometimes related with exercise but without difficulty in breathing. Medical attention was sought due to chest pain and desire to join school s basketball team. Physical exam: Vital signs are within normal limits, physical examination is normal except for tenderness when palpating the left 3, -4, -5 costochondral junctions. Diagnosis: History and the physical examination are highly suggestive of costo- chondritis. The nature of pain, lack of any significant findings through history and physical examination and the ability to induce chest pain while pressing on affected costochondral junctions point to the diagnosis of costochondritis. Treatment: Reassurance that the pain is benign and is not related to the heart is essential. Pain and inflammation of the affected costochondral junction can be eliminated through a 5 7 days course of nonsteroidal anti-inflammatory agent such 420 I. Case 2 History: A 6-year-old boy presents to the emergency room with a 1 day history of severe chest pain localize to the left side of the chest. The mother states that the child was noted to have fever and decrease in appetite of 1 day duration. Past medical history is significant for surgical repair of sinus venosus atrial septal defect 2 weeks ago. Surgical repair was uneventful and the child was discharged home 4 days after surgery in stable condition. Vital signs dem- onstrate rapid respiratory and heart rates, normal oxygen saturation and normal blood pressure measurements. Diagnosis: the past medical history and finding of friction rub is suggestive of pericarditis. The cause of pericarditis and chest pain in this child is post-pericardiotomy or Dressler s syndrome. Treatment: In view of the small volume of pericardial effusion, compromise of cardiac output is not a present concern. If pericardial effusion continues to enlarge despite medical therapy then pericardiocentesis can be used to remove pericardial fluid. Instead, mild turbulence of blood flow, combined with the rapid heart rate and thin chest wall in children allow nor- mal blood flow through normal cardiovascular structures to be audible. Heart murmurs resolve spontaneously as child grows older with slower heart rate and thicker chest wall. Narrowing of passageways of blood results in turbulence which is characterized by eddies or recirculation. Eddies produces vibrations which can be heard through auscultation and in severe cases palpable as a thrill. On the other hand, laminar flow of blood is relatively silent and not audible through auscultation. Narrowing of blood vessels or cardiac valves results in rapid change (drop) in pressure, also referred to as pressure gradient, this causes fluid to accelerate which in turn results in eddies or recirculation phenomenon. Eddies produce the vibrations which result in murmurs or when significant a thrill which can be felt by hand through palpation.

Thus order levitra 10 mg without a prescription, a series of studies are currently under way to test the potential of genetic antivirals directed not only against the structural core and envelope proteins (e safe levitra 20mg. Such antivirals attack the virus after integration into the chromosomes of the host and are aimed at preventing or reducing particle for- mation and/or release from infected cells (Fig cheap 20mg levitra free shipping. Other critical accessory proteins include Vpr (which leads to G2 arrest in the cell cycle of infected cells), Nef (which stimulates viral production and activation of infected cells), Vpu (which stimulates viral release), and Vif (which seems to augment viral production in either early or late steps in the viral life cycle. These regulatory pro- teins may be somewhat less crucial to viral load and replication in comparison with Tat and Rev. Consequently, antiviral agents, which attack these proteins, are less likely to significantly prevent infection and/or the spread of the virus. Second, they must be highly effective and must greatly reduce or, ideally, completely block the production of progeny virus. After fusion of the viral and cellular mem- branes, retroviral core particles are released into the cytoplasm. At the cell membrane, virus particle assembly is completed by the interaction of the core with the viral membrane proteins, and new particles bud (are released) from the infected cell. Replication, however, is greatly impaired when certain mutant forms of such proteins are present. They compete with the corresponding native, wild-type protein inside the cell and greatly reduce virus replication, especially when they are expressed from strong promoters (e. In a similar way, mutant Rev proteins interfere with regulated posttranscriptional events and also greatly reduce the efficiency of virus replication in an infected cell. The activation of the toxic gene leads to immediate cell death, and therefore no new progeny virus particles can be produced. Single-Chain Antibodies Single-chain antibodies (scA, also termed single-chain variable fragments [scFv]) were originally developed for E. They comprise only the variable 242 Dornburg and Pomerantz domains of both the heavy and light chain of an antibody and are expressed from a sin- gle gene. The resulting single-chain antibody can bind to its antigen with similar affin- ity as an Fab fragment of the authentic antibody molecule. Thus, such structures appear to be valuable targets for the attack with genetic antivirals. The high volume of immunoglobulin that must be administered carries risks, as well as the need for prolonged infusion in a monitored setting. At 139 centers in the United States, United Kingdom, and Canada, 1502 children with either prematurity or bronchopulmonary dysplasia were enrolled and randomized to receive five injections of either palivizumab at 15 mg/kg or placebo. The benefit was great- est in children with prematurity alone as a risk factor, compared with children who had bronchopulmonary dysplasia. In further contrast, they are of donor rather than host origin and develop within the window between initial engraftment (3 60 days post transplant) and return of T-cell function (6 8 months post transplant). Traditional priority areas were adjusted to make space for rare diseases, both because they were seen as important in themselves, but also because of the insight they could provide into common complex diseases in the context of a growing awareness of the importance of personalised (or stratied) medicine and the development of targeted therapies for genotypically distinct but phenotypi- cally similar common diseases. Paradoxically this has coincided with a downward trend in the economies of much of the developed world, putting healthcare decision makers between a rock and a hard place. The opportunity to do more, coupled with increasing awareness of nite resources necessitated the creation of new systems for licensing novel ther- apies and determining policy with regard to clinical utility and reimburse- ment. The transi- tional gold standard of the large, multicentre randomised double-blind trial does not work for drugs developed for tiny populations and while patients have no interest in drugs that do not work, new methods for proving quality, safety and ecacy need to be developed if orphan drugs are to make it onto the market. Again traditional methods do not work, simply because its data is lacking in most instances to form a robust assessment of clinical eectiveness and a rational policy for deter- mining patient access, pricing and reimbursement. The challenge facing many healthcare providers and payment agencies today is to develop systems which will provide a framework that carries the trust of patients and families, or which will enable fair decision making in healthcare and resource allo- cation now and sustainably into the future. Patients and other key stake- holders are actively engaging to try and bring this about, but the shape of a sustainable healthcare future for rare disease patients is not yet clear anywhere across the globe. So, we have a potent mix of elements, all of which have come together to raise the prole of rare diseases and the patients of families aected by them. View Online x Foreword Rising to the challenge is a critical priority for all involved if patients are to see their expectations for eective therapies realised, scientists to generate the insights that will create clinical service improvements for doctors and the possibility of a return on investment for industry. This book is a timely contri- bution to the literature in this fast-changing eld. Council Recommendations on action in the eld of rare diseases, European Commission, Luxembourg, 2009. Preface As a term, rare diseases covers an enormous and hugely diverse range of diseases, disorders and conditions. In a similar way, the term orphan drug is also subject to some confusion and misconception within the drug discovery community. When we decided to undertake the editing of this book, we had a number of aims in mind. First and foremost, we wished to produce a broadly accessible book that would set out clearly what is meant by the terms rare diseases and orphan drugs. In so doing, we wanted to highlight the critical role that disease advocacy has played and continues to play in building drug discovery eorts in this area of biomedical science, and discuss some of the unique challenges that this eld presents. Secondly, we wished to present the range of innovative science taking place to create therapies directed at rare diseases through a combination of review and case studies, highlighting the breadth of drug modalities that research in the eld has produced. Research and clinical development in this area has oen been both path-nding and innovative, and in many cases this has been pioneered by small biotech- nology companies, or in some cases small parts of much larger companies. As such, undertaking to write a book chapter from within a small group is a signicant commitment, and we are most grateful to the chapter authors for contributing their time to the writing of this book. Finally, in what is an expanding and evolving area of drug discovery research, we wanted to provide some perspective on where the eld may evolve to in the near future. We found the planning and editing of this book hugely informative and enjoyable, and armed with the knowledge that this book provides, we hope the reader will also share our enthusiasm for this important area of drug discovery. David C Pryde and Michael J Palmer C ontents What are Rare Diseases and Orphan Drugs? Orphan designation is reserved for medicines that will treat diseases with prevalence below the threshold set for rare diseases, and may have additional factors such as the lack of availability of alternative treatments. It has been estimated that there are more than 7000 rare diseases known,7 but only around 5% of these have therapies available8,9 and the unmet medical need across the breadth of rare diseases remains high. Fiy percent of all rare diseases aect children and 85% are classied as serious or life-threatening. Some rare diseases may only aect literally a handful of individuals around the world, while others may aect hundreds of thousands of patients. In the developed world alone, rare diseases are thought to aect some 6% of the population, with estimates of more than 25 million North Americans and more than 30 million Europeans aected by a rare disease. Across the thousands of highly heterogeneous rare diseases that are known, there is no unifying classication that links them all, with the exception that they aect a relatively small number of people. Designing and conducting clinical trials is constrained, as there is usually little understanding or information about the natural progression of the disease to inform end point selection. These challenges increase the uncertainty that a research programme will lead to a new therapy, resulting in historically less investment into these therapies. An interesting example was raised by Tambuyzer,8 who highlighted that for Gaucher disease patients in Germany, only around 5% of all possible patients are being treated despite treatments being available for more than 15 years.

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Supplemental topical antibiotics: mupirocin purchase levitra 10 mg, clindamycin buy cheap levitra 20mg line, isotretinion 146 Mirmirani as interferon-gamma responsible for macrophage activation (56) discount 20mg levitra mastercard. CsA is also known to cause hypertrichosis, which is likely mediated by hair keratinocyte differentiation as well as retarda- tion of catagen. Oral prednisone can be used to rapidly diminish the inammatory signs and symptoms, however given the side-effect prole, it is not considered for long-term use and is used only as a temporary or bridge treatment. Neutrophilic Recognizing the central role of Staphylococcus aureus, treatment regimens aimed at eradication of bacterial carriage have provided a signicant improvement of outcome. It must be noted how- ever, that repeat cultures may be needed to determine the offending bacteria, since the predomi- nant bacteria may change over time. Culture material is obtained from intact pustules, or from extracted hair bulbs or biopsy specimens. A regimen of clindamycin 300 mg twice daily and rifampin 300 mg twice daily for 10 weeks has been shown to be effective in inducing a sustained remission, although further courses may be needed (17,57). The addition of topical mupirocin to the nares for staphylococcal eradication or for longer duration of remission may be advisable. Topical clindamycin solution can be prescribed for ongoing treatment/prevention of recurrence. Other antistaphylococcal antibiotics such as erythromycin, cepahlosporins, trim- ethoprim sulfamethoxozole, or a uoroquinolone with or without concomitant rifampin are variably effective. Dramatic improvements in dissecting cellulitis have been reported with use of isotretinoin, especially if the disease is found in tandem with other features of the so-called follicular occlusion triad. Small starting doses with slow escalation to avoid ares are recom- mended, but with a goal of treatment dose of 1 mg/kg/day for at least 5 months although a longer treatment course may be required (48). If dissecting cellulitis is seen unaccompanied, or if there is a strong suppurative component with growth of S. If the predominant morphology is that of pustules crusting and sinus tracts then topical and/or oral antibiotics should be emphasized in the treatment regimen. Antibiotics are often combined with intralesional corticosteroids for treatment of concomitant inammatory papules or hypertrophic scars. Current surgical treatments consist of scalp aps, reduc- tion procedures with or without prior tissue expansion, and autologous hair transplantation; these procedures are often combined or done serially (58). Patients with traumatic types of alopecia are generally seen to be the most appropriate candidates for surgery since there is little likelihood for progression of hair loss. There are no studies to determine the optimal period of quiescence before undertak- ing surgery; some have advocated 6 9 months, while others have waited 3 years (58,59). Other limitations to surgical hair restoration include the lack of appropriate donor sites and atrophy of the recipient area. The future of Cicatricial Alopecia 147 surgical hair restoration may lie in cloning hair follicles, thus providing an unlimited supply of donor grafts; technological advances will likely make this a reality in the next decade. Surgical treatment may also play a role in providing symptomatic relief for patients with suppurative, boggy, pus-lled lesions, or sinus tracts. Incision and drainage of these types of lesions may relieve symptoms and hasten healing. Surgical removal of hypertrophic scars can be an option in folliculitis keloidalis for improved cosmesis. Study of these disorders on a molecular level will no doubt provide much needed insight into the pathophysiology and provide targeted treatment options as well. Possible role of the bulge region in the pathogenesis of inammatory scarring alopecia: lichen planopilaris as the prototype. Folliculitis decalvans including tufted folliculitis: clinical, histological and therapeutic ndings. Postmenopausalfrontal brosing alopecia: a frontal variant of lichen planopilaris. Immunouorescent ndings and clinical overlap in two cases of follicular lichen planus. Successful treatment regime for folliculitis decalvans despite uncertainty of all aetiological factors. The normal hair shaft has a consistent diameter throughout its length, with the most common shape in cross section being oval. Signicant variations exist particularly in different racial groups from straight to woolly hair as well as in thickness of the hair shaft. The medulla is a normal feature of the hair shaft and is character- ized by a central cavity, but is only present in some individuals. Its appearance can vary from a continuous cavity throughout the hair shaft to being only intermittently present. Weathering Hairs grow, on average, 1 cm per month, so the tip of a hair ber that is 35 cm long has been exposed to environmental insults for approximately 3 years. These include damage to the hair cuticle leading to fraying or loss of cuticular cells from the distal hair shaft. Other features of weathering include longitudinal splits and trichorrhexis nodes (Fig. If weathering is seen in the proximal hair shaft (particularly within the rst 2 cm from the scalp) this is considered pathological and may either be present nonspecically or be related to a characteristic hair-shaft anomaly. Examination of the Hair Shaft Most disorders (perhaps apart from disorders leading to uncombable hair, which is better diag- nosed with electron microscopy) can be diagnosed on light microscopy of hair samples. It is important to take hair samples from multiple sites as pathology can be of intermittent severity and it is helpful in noting which is the proximal end of the hair to determine if weathering changes are pathological. It is only when considering a disorder such as loose anagen syndrome that hairs need to be obtained by hair pull. Classication of Hair-Shaft Disorders A major division of hair-shaft disorders is into those associated with hair fragility and those that do not affect the integrity of the hair shaft. Within each of these categories for each specic hair abnormality consideration should be given to whether the hair-shaft disorder is occurring as an isolated phenomenon, in association with other cutaneous or noncutaneous abnormali- ties, or as a syndrome. It is important to note that hair-shaft disorders can have signicant variations in severity from barely noticeable even subclinical anomalies to severe effects (particularly in the hair-shaft 150 Dinh et al. These variations can even occur between patients with the same genetic mutation in the same family. The condition may be present throughout the entire scalp or maybe patchy or even localized. Patients with fragility disorders usually present with short hair that breaks easily. For these patients, haircare advice is required to minimize the impact of grooming habits (Table 1). When shampooing, always use a conditioner, and leave it on the scalp for at least ve minutes before rinsing. Protect the hair from excessive exposure to sunlight, by wearing a loose-tting hat or scarf. If a fracture occurs transversely through the node, the end of the hair resembles a small paintbrush. However an assessment of what is pathological needs to also consider the patient s racial background. Vigorous attempts to straighten curly hair may cause nodes to occur sooner and closer to the root.

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The cause of vomiting is unclear discount levitra 20 mg online, but may be 140 per minute quality levitra 20mg, and a respiratory rate of 20 per secondary to brain stem irritation and/or elevated minute cheap levitra 20 mg free shipping. The neck surprising long before becoming concerned enough to was very stiff, with both Kernig s and Brudzinski s signs bring the patient to the hospital. Coarse diffuse rhonchi were evident throughout delays dramatically worsen the prognosis of bacterial all lung elds. In more severe cases, loss of consciousness exam showed no cranial nerve abnormalities. This movement stretches A lumbar puncture was performed in the emer- the meninges and is resisted by the patient with gency room. Kernig s sign requires that the knee be bent at a tein 970 mg/dL (normal: 14 to 45 mg/dL),and glucose 45-degree angle as the patient lies supine. A careful ear, nose, and throat examination should be E:Eye opening Spontaneous 4 performed. Findings of otitis media (dull tympanic Responds to verbal command 3 membrane, uid behind the ear drum) may be discov- Response to pain 2 ered in cases of S. The nasal passage and posterior pharynx may also reveal a M:Best motor Obeys commands 6 purulent discharge suggestive of sinusitis, an infection response Localizing response to pain 5 that less commonly leads to meningitis. Withdrawal response to pain 4 Flexion to pain 3 Auscultation of the heart may reveal a diastolic mur- Extension to pain 2 mur suggesting aortic insufciency, which would No motor response 1 strongly suggest bacterial endocarditis as the primary a Worst possible score is 3; best possible score is 15. Most cases of endocardi- tis complicated by meningitis are the result of infection category should be scored individually for example, with S. Interpretation: 13 mild brain injury; 9 12 moderate brain injury; 8 severe brain injury. About Clinical Manifestations in A thorough examination of the skin needs to be per- formed looking for purpuric lesions. Petechiae and pur- Bacterial Meningitis pura are most commonly encountered in patients with meningococcemia, but they may also may be found in 1. The ight leg raise) signs are insensitive; head jolt exact level of neurologic function should be docu- maneuver may have higher sensitivity mented by determining a Glasgow score (Table 6. The patient who is unrespon- nasal discharge resulting from a cere- sive to deep pain (Glasgow score 3) has a much higher brospinal uid leak (S. Focal nd- d) Neurologic exam should look for focal nd- ings such as hemiparesis, asymmetric pupillary response ings (suggests a space-occupying lesion) to light, or other unilateral cranial nerve decits are and assess mental status (Glasgow score is uncommon in bacterial meningitis, and they raise the an important prognostic factor). The nding of papilledema on fundo- If no focal neurologic decits are apparent, and if scopic exam is rare in meningitis and usually indicates papilledema is not seen on fundoscopic examination, a the presence of a space-occupying lesion. In very young patients, neonatal and infant Patients with bacterial meningitis who have not meningitis presents simply as fever and irritability. If the clinician has included Because bacterial meningitis causes marked inam- meningitis as part of the differential diagnosis, a lumbar mation of the meninges, glucose transport is impaired, puncture needs to be performed. Because this organism usually remains intracellu- About the Diagnosis lar, Gram stain is positive in only 25% of cases. If meningitis is a consideration, a lumbar punc- patients with a negative Gram stain. If focal neurologic decits and papilledema are absebt, a lumbar puncture can be performed exclude the possibility of bacterial meningitis. Opening pressure of the cerebrospinal fluid remains the most sensitive test for diagnosis. In patients over the age of poor penetration of antibiotics across the blood 60 years, maximal doses of ampicillin are added to the brain barrier. Intermediately resistant stains (penicillin third-generation cephalosporin to cover for L. This organism is not sensitive to cephalosporins, and cillin therapy; however, as the integrity of the blood brain penicillin or ampicillin are the treatment of choice. When intracranial pressure is documented by high-dose ceftriaxone or cefotaxime is recommended for lumbar puncture to be markedly elevated, intravenous intermediately penicillin-resistant S. Oral glycerol may also reduce cerebral edema, and For infections with highly penicillin-resistant S. Vancomycin penetrates the intact blood brain barrier These agents are administered only after the rst seizure. Rifampin combined with vancomycin may also be effective for the treatment of highly resistant S. The antibiotic response should be monitored in About the Treatment patients infected with highly penicillin-resistant pneu- mococci. In these patients, the lumbar puncture should of Bacterial Meningitis be repeated 24 to 36 hours after the initiation of therapy. Antibiotics should be given within 30 minutes if cyclines, and rst-generation cephalosporins should not bacterial meningitis is suspected. Dexamethasone also 3 months to 60 years is ceftriaxone or cefo- signicantly reduces the incidence of deafness. If with pneumococcal meningitis and Glasgow coma scores more than 60 years or immunocompro- of 8 to 11, dexamethasone administration (10 mg q6h mised, use ceftriaxone or cefotaxime, plus 4 days) was also found to reduce morbidity and mortal- ampicillin and vancomycin. Dexamethasone should be given just before or simul- b) nosocomial disease, is vancomycin and taneously with antibiotics, because inammatory media- ceftazidime or cefepime. Other inhibitors of otics in inammation, such as monoclonal antibodies directed a) children (shown to be efcacious in Haemo- against the adherence receptors of leukocytes, are poten- philus inuenzae). Additional therapeutic measures are primarily directed b) adults (efcacious in Streptococcus pneumo- niae with Glasgow coma score of 8 to 11). Mortality is higher in very States), and about half of these deaths could be prevented young and elderly individuals. The young patient at higher risk for developing invasive pneumococcal infec- whose brain is developing often suffers mental retarda- tion including meningitis and should be vaccinated. A single intramuscular or subcutaneous injection is pro- Prevention tective for 5 to 10 years. Permanent sequelae are common: bloodstream reduces the likelihood of seeding the meninges. Chemoprophylaxis use: to be short-lived, with antibody titers decreasing after 3 a) H. The incidence household contacts with unvaccinated child of meningococcal disease remains low in the United under 2 years of age, and for children under States (approximately 1 in 100,000 population), and 2 years of age exposed in a daycare center. Two days mised host and patients over 65 years of age who often later, she developed a sharp, throbbing bi-temporal develop a more rapid decline in protective antibody levels. Her headache Revaccination may considered after at least 5 years have was made worse by sitting up or moving. She also noted some muscle stiff- vaccine that is immunogenic in children under the age of ness in other areas in particular her lower back. She felt 2 years is recommended for routine pediatric immuniza- very tired and lost her appetite. This vaccine has signicantly reduced invasive pneu- lethargic at times,she never lost touch with reality.