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2003;5(1):1

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INDIAN JOURNAL OFPRACTICAL PEDIATRICS

••••• A quarterly medical journal committed to practical pediatric problems andmanagement update presented in a readable manner

••••• IJPP is a subscription Journal of the Indian Academy of Pediatrics••••• Annual subscription:Rs. 300/- 10 years subscription:Rs.3000/-

Vol.5 No.1 JANUARY-MARCH 2003

Dr. A. Balachandran Dr. D.VijayasekaranEditor-in-Chief Executive Editor

CONTENTS

FROM THE EDITOR'S DESK 3

TOPIC OF INTEREST - HEMATO-ONCOLOGY

Editorial : Pediatric hematology & oncology: Where do we stand? 5

- Bharat R. AgarwalRole of peripheral smear in diagnosing difficult clinicalsituations in pediatrics 8- Sarala Rajajee

Update of component therapy in pediatrics 13

- Nitin K ShahAn approach to a child with recurrent bleeding 21- Revathi Raj

Management of immunocompromized children with cancer:Role of the primary care physician 25

- Sharada A SarnaikComplete blood counts in pediatric practice 29- Gandhimathi Sekhar

IJPP

Journal Office: Indian Journal of Practical Pediatrics, IAP-TNSC Flat, ‘F’ Block, Ground Floor,Halls Towers, 56, Halls Road, Egmore, Chennai - 600 008. INDIA. Tel.No. : 044-28190032E.mail : ijpp_iap@rediff mail.comAddress for registered/insured/speed post/courier letters/parcels and communication byvarious authors: Dr. A. Balachandran, Editor-in-chief, Indian Journal of Practical Pediatrics, “F”Block, No. 177, Plot No. 235, 4th Street, Anna Nagar East, Chennai - 600 102. Tamil Nadu, INDIA.

Indian Journal of Practical Pediatrics 2003;5(1):2

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Recent advances in childhood acute lymphoblastic leukemia 38

- Kusumakumary P

CRITICAL CAREHypovolemic hypernatremic dehydration in infants 44

- Nair PMC

PRACTITIONER’S COLUMNApproach to the child with fever and rash 49

- Benjamin B

IJPP-IAP CME 2001Management of acute asthma 57

- Vijayasekaran DSome common dermatological problems in children 63

- Jayakar Thomas

RADIOLOGIST TALKS TO YOUThe bladder and a general approach to imaging 66

- Vijayalakshmi G, Natarajan B, Ramalingam A

CASE STUDYMetatropic dysplasia 71

- Raveendranath, Ravisekar CV, Venkataraman P,Vasanthamallika TK, Elizabeth John

Crouzon’s syndrome 73

- Archana B Patel, Ramesh L RengeSchizencephaly - A case report 77

- Geethanjali M, Anuradha K

QUESTION AND ANSWERS 80

BOOK REVIEW 84

NEWS AND NOTES 17,20,24,28,37,48,79,83

FOR YOUR KIND ATTENTION

* The views expressed by the authors do not necessarily reflect those of the sponsor orpublisher. Although every care has been taken to ensure technical accuracy, no responsibility isaccepted for errors or omissions.

* The claims of the manufacturers and efficacy of the products advertised in the journal arethe responsibility of the advertiser. The journal does not own any responsibility for the guaranteeof the products advertised.

* Part or whole of the material published in this issue may be reproduced withthe note "Acknowledgement" to "Indian Journal of Practical Pediatrics" without prior permission.

- Editorial Board

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FROM THE EDITOR’S DESK

I am very pleased to state that, Indian Journalof Practical Pediatrics has successfully completed10 years from its inception, thanks to the excellentpatronage by all the contributors, reviewers andour readers. We are now entering into 11th yearof publication. We have grown from infancy topreadolescent age during this decade. This journalhas been under the editorship of three eminentpersons consecutively since 1993 viz., Dr. A.Parthasarathy (1993-1995), Dr. B.R. Nammalwar(1996-1998) and Dr. M. Vijayakumar (1999-2001). To recall, IAP Journal of PracticalPediatrics was launched in 1993 at the NationalConference of IAP at Kolkatta. Since then thejournal has been progressing each year with manynewer topics and innovative ideas.

In 1999, with the concurrence of IAPExecutive Committee, Dr. M. Vijayakumar, theimmediate Past Editor-in-Chief, the journal’sname was changed from IAP Journal of PracticalPediatrics to Indian Journal of PracticalPediatrics, for registering the journal with“Registrar of Newspapers in India”.

The journal has become very popular amongthe practicing pediatricians and post graduates.Infact it has become a desktop reference forpractitioners.

The editorial board is thankful to all the pastand present IAP office bearers, executivecommittee and advisory board for their supportand encouragement to the journal. We place onrecord with gratitude the yeoman servicerendered by the previous editors-in-chief of IJPP,to popularise the journal.

The topic of interest for this issue is Hemato-oncology. We are thankful to Dr. Janani Shankar,consultant, Kanchi Kamakoti CHILDS TrustHospital, Chennai, who has helped us to formulatethis issue. She has carefully chosen the topicswhich are more relevant to the clinical practiceas well as to the post graduates. The authors withtheir vast experience and knowledge hascontributed articles in this issue. The readers willdefinitely be benefitted by these articles.

The editorial board is planning to bring outpractical guidelines in the management of commonpediatric problems which will be of immunse useto all the practicising pediatricians of our country.

The recent hike in the postal tariff andescalation in the cost of printing and stationaryhas increased our overall expenditure. The steepfall in the interest rates of our fixed deposits hasbeen causing huge deficit in our budget. In orderto boost the revenue from the fixed deposits asinterest, we are constrained to increase our corpusfund. So we sincerely request all our earliersubscribers who have enrolled with Rs. 500 tocontribute Rs 1000/- and those who have initiallypaid Rs 1000 to pay Rs 500/- as an additionalsum to increase our corpus fund. This will help toaugment the drop in the bank interest from fixeddeposits to meet our expenses. We also thank allour readers who have responded to our earlierappeal for thier generous contribution to ourcorpus fund, which we have alreadyacknowledged in our journal.

Wishing all our readers a happy andprosperous New Year, 2003.


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CHECK LIST

CHECKLIST FOR INDIAN JOURNALOF PRACTICAL PEDIATRICS

The checklist must accompany themanuscript.General

Original articles which have not beenpublished elsewhere are invited and shouldbe sent to the Editor. They are consideredfor publication on the understanding that theyare contributed to this journal solely.Four complete sets of the manuscript aresubmitted.Manuscript is typed double-space throughoutwith wide margin on one side of paper onlyincluding the list of references and tables.Manuscript is arranged as follows: Title page,text, acknowledgements, references, tables,figure legends, figures.All pages are numbered at the top of the rightcorner, beginning with the title page.The letter of submission has been signed byall authors.

Submission of “Floppy Disc”Two copies of the articles plus a floppy disc

of the wordprocessed manuscript and a list ofany nonstandard characters that were used in thedisc should be submitted in the usual manner. Thepreferred storage medium is a 3.5 inch disc inMS-Word compatible format. The publisher isunder no obligation to use the submitted floppydisc, but will make every attempt to do so.Text

Only generic names should be usedMeasurements must be in metric units withSystem international (SI) Equivalents givenin parentheses.

Title pageName and designation of author(s).Department where the work was done.Running title

ReferencesIdentified in the text by Arabic numerals in

parentheses.Type double-space on separate sheets and

numbered consecutively as they appear in thetext.

Abbreviations of journals conform to the styleof Indian Journal of Practical Pediatrics.

Typed as illustrated in “Instructions toauthors” with correct punctuation.

Checked carefully by the author(s).Tables

Numbered with Roman numerals and typedon separate sheets.

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author’s name and top location indicated on theback of each figure. Legends typed double-spaceon separate sheet. No title on figure.

Each manuscript must be accompanied by aletter of declaration to be signed by each authorto confirm that he has seen, read and approved it.

All manuscripts which are rejected will notbe returned to author. Those submitting articlesshould therefore ensure that they retain at leastone copy and the reference numbers, if any, ofthe illustration.

Author’s Signatures.

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PEDIATRIC HEMATOLOGY ANDONCOLOGY: WHERE DO WESTAND?

Rapid strides in the diagnosis andmanagement of childhood cancers and blooddiseases have been made worldwide in the pasttwo to three decades. Recently cure rates in someof the pediatric malignancies like childhood acutelymphoblastic leukemia, lymphomas and othershave improved from almost negligible to more thanseventy five percent. The same is true for anumber of blood diseases in children likethalassemia, hemophilia and platelet disorders:through some are incurable, many can be wellcontrolled and prevented. It is very hearteningthat some of this international success hasdefinitely percolated to our country. This hasbenefitted a large number of children from boththe public and the private hospitals for thediagnosis and management of these veryspecialized diseases.

Pediatric hematology-oncology does not asyet claim a separate existence in many medicalcolleges or private hospitals. Consequently mostchildren with blood diseases and cancer are stillbeing diagnosed and treated by adulthematologists and oncologists!

Recent advances

Like many other pediatric subspecialities theclinical practice in pediatric hematologyoncology is being transformed by the applicationof genetic discovery to old and new problemsalike1. Modern pediatric oncology believes that“Cure is not enought”. Hence pediatriconcologists are not satisfied with possibility of

cure but aim to apply the genetics of risk-basedtherapy to reduce therapy-related complicationswhile retaining the potential for cure. Similarly,elucidating the genetic basis of manyhematological disorders holds the promise of noveltargets of pharmacological intervention andreducing the toxicity of tratment. More than ever,the integration of new knowledge in the day-to-day practice of general pediatrics will ensuretimely and cost-effective evaluation of commonhematological problems and promote the use ofsupportive care, thereby improving outcomesand, most importantly, ensuring adequate accessto care in an universal era of shrinking resources.

Roadblocks in India

Pediatricians are usually very quick tosuspect a hematological problem. They are goodclinicians! But a reliable specialised advice and agood laboratory backup is essential for a quickhematological diagnosis. The delay and thehurdles start at this point. He thinks: To whomshould I refer the child? Where are the tests thatI need to do available in the city? How long willthe results take? What treatment plan is to befollowed? How should I monitor and the followupthis child? - umpteen questions from the‘generalis’ pediatrician still remain to beanswered. This is due to several reasons, we havelimited specialists in the country who are well-trained, the laboratory support is often notavailable or easily accessible or if available at avery high cost, facilities and services usually arenot available under one roof resulting in patientsrunning from pillar to post, lack of ‘Day Care’centres leads to unacceptable and prolongedhospitalisations, tratment options are often soexpensive that patients opt out; blood components

EDITORIAL


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which are an essential constituent of thetherapeutic armamentarium are perennially undershort supply. These deficiencies lead tosuboptimal management of these children. But Imust add that despite these lecunae, we havecontinued to make significant progress.

The future: What should be done?

The demand for better care is increasing withregard to diagnosis, management and preventionof these specialized diseases. To meet thischallenge, medical colleges and private hospitalsin the country need to establish more specializedpediatric hematology and oncology units forcatering to the increasing number of children withthese problems. A number of hematological andoncological disorders are chronic in nature andrequire a long term treatment plan and follow-up,which can be carried out best by pediatricianswith special interest in hematology-oncology.Therefore, there is an urgent need to establishdedicated units for this purpose. Establishmentof more facilities would mean requirement ofqualified specialists in pediatric hematology-oncology. We cannot shirk the onus of trainingthem in house (in the country) !.

Secondly diagnostic facilities in some areasremain inadequate or sometimes inaccessible tothe poor e.g. RBC enzyme studies (pyruvate-kinase etc) for diagnosis of hemolytic anemias,immunophenotyping for characterization ofleukemias, pediatric histopathological reviewfacilites, immunohistochemistry, immuno-deficiency studies, etc. I the near future we haveto take care of these requirements too. I cansuggest centralization of resources in the countryto efficiently carry out quality controlledlaboratory analysis required for hematologicaldiagnosis at nominal costs. Those who can payshould be charged for the tests, while the sameservice can be provided at a subsidized cost tothe poor.

“Comprehensive care” for thalassemia,hemophilia, leukemia, and other diseases is thebuzzworld in pediatric hematology-oncologymanagment. I can say that we do not yet havean ideal comprehensive care setup for any ofthese diseases. What would comprehensive caremean? Provision under one roof of services of apediatric hematologist, pediatric surgeon,pediatric radiologist, pediatric pathologist,pediatric nurse, social worker, psychologist, etc.With regard to pediatric oncology, theparticipation and co-operation of pediatricsurgeons is of utmost importance. I feel the lackof this co-ordination can be rectified right away.

The most relevant but crucial limitation tothe progress of pediatric hematology-oncologycare is the lack of resources and funds for growthand development. This situation has worsenedover the last few years and might worsen furtherin the years to come due to the increasing costsof health care services. The most promisingopportunity to tackle this resources crunch comesfrom the parents and volunteers and from theirco-operation with the health professionals.Encouraging strong and viable parentorganizations or support groups are essential fromthis point of view. Hence we will have to learn toharness the power of parent groups andassociations to raise funds for our specializedefforts. We cannot and should not depend on thegovernment alone to initiate and support allendeavours. Active support and involvement fromthe pediatricians can help in strengthening theiractivities and efforts for the wellbeing of all ourown patients with these illnesses. The leastwe can contribute is by advising parents ofchildren with these diseases to join hands in thesevarious ‘self-help’ groups to minimize thefinancial, social and psychological burden of thesechronic disorders.

I suppose we can and need to consolidateon the research front as well. considering more

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Published and owned by Dr. A. Balachandran, from Halls Towers, 56, Halls Road,Egmore, Chennai - 600 008 and Printed by Mr. D. Ramanathan, at Alamu Printing Works,9, Iyyah Mudali Street, Royapettah, Chennai - 600 014. Editor : Dr. A. Balachandran.

NEWS AND NOTES

INDIAN ACADEMY OF SPORTS & FITNESS MEDICINE

ANNOUNCESA Post Graduate distance learning Certificate Course (For Doctors) in Sports & Fitness Medi-cine for the first time in India

An opportunity to become a consultant / counsellor in SPORTS & FITNESS MEDICINE

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than 1/3rd of country’s population is below fifteenyears of age i.e. approximately four hundredmillion children and the incidence ofhematological and oncological diseases, like manyother diseases, is enormous and there is ampleopportunity for clinical and basic research. Cost-effective solutions need to be worked out for anumber of our problems, in our own setting, bycollaboration and cooperation.

Conclusion

“The truth is rarely pure and never simple”- Oscar Wilde

We are taking slow, small, but purposefulsteps towards expanding in the field of pediatrichematology/oncology. Provision of high standard

of patient care services, programme for trainingof fellow colleages and continuing research foroptimal low cost solutions should be our goalsand the basis of our efforts for the future.Fulfillment of these ideas would be a dreamcome true.

Bharat R. AgarwalHead of Department,

Pediatric Hematology Oncology Services,B.J. Wadia Hospital for Children and

Institute of Child Health and Research Centre,Parel, Mumbai - 400 012.

Reference

1. Vichinsky E, Walters MC, Feusner J. PediatricHematology Oncology. Pediatr Clin N Am 2002;49 (5): xiii-xvi


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ROLE OF PERIPHERAL SMEARIN DIAGNOSING DIFFICULTCLINICAL SITUATIONS INPEDIATRICS

* Sarala Rajajee

Examination of the peripheral smear andestimation of the full blood counts are the mostbasic and yet the most informative investigationsperformed in hematology.

The blood film

Morphology is best examined in the part ofthe peripheral blood film where red cells are closerto each other but not overlapping. Red cells areexamined for abnormality of size(macrocytosis, microcytosis) by comparing themto small lymphocytes which are of similarsize, abnormal shape (poikilocytosis eg,schistocytes, bite cells, burr cells) and stainingcharacteristics (hypochromia, polychromasia).The morphology of the white cells and plateletsare also examined. In a finger prick smearplatelets are seen mainly in the tail end asaggregates.

Knowledge of normal variation is essentialin the interpretation of blood films. Thus in thenewborn, the presence of nucleated red cells(normoblasts) is physological but they disappearfrom the peripheral blood by a few days of age.

The red cells

The most common abnormality seen in our

HEMATO-ONCOLOGY

population is hypochromic microcytic red cells(Fig.1) with anisopoikilocytosis due to irondeficiency. There is also associated thrombocy-tosis. This may be due hypoxic stimulus to thebone marrow or if iron deficiency is due tochronic blood loss.

Case I: A two year old girl presented with severeanemia. The blood smear was suggestive of irondeficiency. This was confirmed by low transferrinsaturation. Her motion was however positive foroccult blood and endoscopy revealed grade 3oesophageal varices.

Key Point : In any case of iron deficiencyanemia apart from diet history, examination foroccult blood loss is essential.

The other often seen causes of hypochromicmicrocytic anemia is hereditary hemolytic anemiaeg; β Thalassemia. The differentiating factors inthe blood film is the presence of polychromasiaand normoblasts (Note - This may be seen in irondeficiency due to blood loss and within 3-4 daysafter iron therapy due to reticulocyte response).Platelets are normal or low in thalassemia unlikethe thrombocytosis seen in iron deficiency.

* Senior Consultant,Kanchi Kamakoti CHILDS Trust HospitalChennai - 600 034. Fig. 1 Hypochromic microcytic anemia.

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Congenital red cell disorders responsible foranemia may be spherocytosis or elliptocytosis.

Case 2: A twelve year old child presented withsevere anemia, mild jaundice and splenomegalyfollowing a febrile illness. She had beeninvestigated for anemia earlier and was onhematinics. Her peripheral smear revealed morethan 40% spherocytes with polychromasia. Herfather’s smear was positive for spherocytes.

Note: Malaria can cause acute hemolysis withmicro spherocytes. Auto immune hemolyticanemia due to SLE may be associated withspherocytes. Examination of parents will give aclue to the hereditary nature of the problem.

Congenital hemoglobinpathy eg: sickle cellanemia and hemoglobin C can be picked up onthe peripheral smear.

Case 3: A two year old girl presented with painfulswelling of hands and feet. Her peripheral smearshowed sickle cells. X-ray of hands revealedhypodense areas in the phalanges. This is venoocclusive problem in sickle cell disease presentingas Hand Foot disease. Peripheral smear inhemoglobin C shows many target cells.

Note: Target cells may be seen in other situations,eg; Thalassemia, iron deficiency, liver disordersetc.

G6PD deficiency though rare is seenparticularly in some communities.

Case 4: A three year old boy was brought toemergency room with severe anemia and historyof febrile illness treated with antimalarials andpassage of red coloured urine. Peripheral smearshowed red cell fragments (Fig 2), blister cellsor ghost cells. In the absence of G6PD theoxygenated hemoglobin in red cell is removedby the spleen and these red cells take theappearance of blister cells. This is charecteristicof G6PD deficiency and is an important pointerto avoid drugs which can aggravate the problem.

Malaria is the commonest infectionassociated with hemolysis. A skilled microscopistcan pick up malarial parasite on smear at a parasiteload of 10/ul. The other features on smear tosuspect malaria are the evidence of hemolysis ie:polychromasia, microspherocytes, normoblastswith associated pigment in neutrophils andthrombocytopenia. A thick smear is warrantedto pick up the presence of he parasite.

Presence of Howell-Jolly bodies in the redcells indictes absence of spleen or splenicdysfunction. Howell-Jolly bodies are ribosomeremnants in the red cell appearing as a roundedred inclusion in the RBC.

Case 5: A one year old girl was admittedwith pyogenic meningitis to the intensive care unit.The bacteria in the CSF was Pneumococcus.Ultrasound abdomen revealed absence of spleenand peripheral smear showed Howell - Jollybodies. Asplenia in infants makes themsusceptible to capsulated organisms likepneumococcus.

Red cell fragmentation syndrome can occurin a child with hemangioma where the peripheralsmear shows red cell fragments (schistocytes)and anisopoikilocytosis.

Fig. 2 RBC fragmentation


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Case 6: A three month old body was diagnosedas hemangioma in the neck at birth whichgradually increased in size. Prior to admission,there was sudden increase in size with signs ofairway obstruction. Peripheral smear showed redcell fragments with thrombocytopenia. This isseen in Kasabach Merrit Syndrome, acomplication of hemangioma where there islocalized intravascular coagulation withconsumption of platelets. Thrombocytopenia andprolonged PT, PTT leads to increased bleeds andincrease in size of hemangioma.

Note: Red cell fragments can be seen in othersituations like Hemolytic Uremic syndrome,prosthetic valves etc.

Leucocytes

Neutrophils: The commonest indicator of sepsisis neutrophilic leucocytosis in the peripheral smear.There is associated toxic granulation orvacuolation in the cytoplasm. In newborns andyoung infants with sepsis, there may beneutropenia and toxic changes are often seen inthe neutrophils which may indicate sepsis.

Note: Neutrophilic leucocytosis may also occurdue to acute stress eg: post-ictal and toxicgranulation may be seen in inflammatoryconditions eg: vasculitis, juvenile rheumatoidarthritis, Kawasaki disease.

In the initial phase of bacterial infections eg:enteric fever, there is often neutrophilicleucocytosis. There may be associatedthrombocytopenia. After a course of appropriateantibiotics the fever may persist. At this stagethe peripheral smear may show neutrophils withtoxic changes, many reactive lymphocytes andthrombocytosis which indicate possiblerecovering infection. The fever often settleswithin a few days without change of drugs.

In immunocompromsied children onchemotherapy with fever an absolute neutrophil

count of less than 500 indicates febrileneutropenia and warrants further investigationand treatment.

Hypersegmented neutrophils or neutrophilswith scanty or no granules in the presence ofrecurrent infections indicates neutrophil functiondisorder.

Eosinophils: Eosinophilia (absolute eosinophilcount more than 400) on the peripheral smearindicate underlying allergies or helminthiasis,Hypereosinophilia is seen in infections likefilariasis, eosinophilic facitis, hypereosinophilicsyndrome and eosinophilic leukemia.

Lymphocytes: Lymphocytic predominance isnormal in infants. In the presence of viral feverthere is lymphocytic response with reactivelymphocytes.

Case 7: A 8 year old body presented with fever,generalized lymphadenopathy and hepatosplenomegaly. His peripheral smear revealed manyatypical lymphocytes (Fig 3) i.e large lymphocyteswith pale abundant cytoplasm with monocytoid,plasmacytoid or lymphocytoid nuclei. This ischaracteristic of infectious mononucleosis.Cytomegalovirus infections may also present ina similar manner.

Fig. 3 Atypical lymphocyte

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Case 8: A three year old child presented withfever, generalized lymphadenopathy,hepatosplenomegaly and bony tenderness.

The peripheral smear showed numerouslymphoblasts. These cells has scanty cytoplasmwith opened out nuclear chromatin and indistinctnucleoli suggestive of lymphoblastic leukemia.

Other types of leukemia indentifiable onperipheral smear are acute myeloid leukemia andchronic myeloid leukemia.Platelets

Thrombocytopenia is seen in malaria, viralfevers like dengue haemorrhagic fever andbacterial infections. This is self limiting andrecovers after treatment of infections. In DHFserial platelet count is useful in assessing theprogress of the disease.Case 9: A 2 year old girl presented withspontaneous skin and mucous membrane bleeds.A finger prick smear showed thrombocytosis butthe platelets were all discrete with no aggregates.This is indicative of thrombasthenia, a inheritedplatelet function disorder where there is inabilityof the platelets of aggregate. A simple test likethe finger prick peripheral smear will give thediagnosis avoiding further coagulation work up.Note: In any child presenting with problem ofbleeding diathesis peripheral smear examinationshould be done before ordering further tests.Thrombocytosis in children is often benign andsecondary to bleeds and inflammatory conditions.Only in conditions like Kawasaki disease does itwarrant treatment with aspirin.Case Scenarios

Abetalipoproteinemia: A 5 year old boy bornto 2nd degree consanguinous parents presentedwith failure to thrive from infancy. There was ahistory of one sibling death due to similarproblems and serial abortions in the mother.Routine examination of the peripheral smearrevealed more than 50% acanthocytes. Basedon this, tests were streamlined to doing lipid profile

and lipoprotein electrophoresis which revealedhypolipidemia and absent b lipoprotein band.Jejunal mucosal biopsy confirmed the diagnosisof abetalipoproteinemia which revealed lipidladen enterocytes. This case illustrates theimportance of simple tests like peripheral smearexamination in streamlining further tests in thediagnosis of major diseases.Wiskott Aldrich Syndrome: A 2 year old boywas admitted with bronchopneumonia. He had aearlier history of recurrent infections with skinand mucous membrane bleeds. He had beendiagnosed as dengue hemorrhagic fever theprevious year as he had thrombocytopenia.Clinical examination revealed an undernourishedchild with atopic dermatitis, petechiae andhepatosplenomegaly. His peripheral smearrevealed neutrophilic leucocytosis, moderateeosinophilia and thrombocytopenia. In view ofearlier documented thrombocytopenia, eczemaand recurrent infections, a diagnosis of WiskottAldrich Syndrome was made. The family latergave a history of similar problems in the eldersibling who died in infancy.Chediak Higashi syndrome: 6 year old girl wasreferred for intermittent fever for 2 months,distention of abdomen, face and limbs for 1½months and hematemesis of 2 days duration. Shewas pale, icteric with hypo and hyperpigmentedgeneralized macular lesions, petechiae over theleft foot with hepatosplenomegaly. Her peripheralsmear showed perdominant lymphocytes withmany of them containing eosinophilic coarsegranules. Bone marrow revealed a hypocellularmarrow with occasional megakaryocytes withcoarse brown inclusions in the cytoplasm oflymphocytes and few neutrophils. In view of theskin lesions, peripheral smear and bone marrowsmear examination she was diagnosed to haveChediak Higashi Syndrome with a probableaccelerated phase presenting as fever,pancytopenia, hepatosplenomegaly andlymphohistiocytosis.


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Hemolytic Uremic Syndrome: Serial peripheralsmears are helpful in following the evolution ofHUS. Initial smear in a child presenting withacute gasteoenteritis reveals features ofneutrophilic leucocytosis with toxic granulationand normal platelets. As the renal involvementdue to HUS occurs thrombocytopenia evolvesdue to localized intravascular coagulation andplatelet consumption. Later due to the stress effecton the red cells by fibrin strands there is red cellfragmentation and burr cells. During the recoverystage platelets return to normal with neutrophilsshowing decreasing toxic changes. Burr cellspersist for a longer time. The triad of neutrophilicleucocytosis with toxic changes, burr cells andthrombocytopenia in a post diarrheal renal failureindicates possible HUS.Lipid Storage Disorder: In lipid storagedisorders presence of vacuoles in the cytoplasmof lymphocytes is an indication to do bonemarrow to confirm presence of storage cells (Fig4) like Gauchers or Niemann Pick disease.Immerslund Grasbeck Syndrome: A six monthold baby was referred as acute myeloid leukemia.Peripheral smear revealed macrocytes,hypersegmented polymorphs (Fig 5) andabnormal looking myeloid precursors withthrombocytopenia. Clincally the baby hadpigmentation over hands and feet with associated

anemia. The peripheral smear was indicative ofmegaloblastic anemia which was confirmed bybone marrow aspiration. Urine protein-creatinineratio was increased. The combination ofmegaloblastic anemia with proteinuria is indicativeof Imerslund Grasbeck syndrome. Withparenteral infections of vitamin B-12 the cild isdoing well on followup. Detailed examination ofa peripheral smear can thus be an indicator ofdisease and can lead to proper streamlining offurther investigations for diagnosis.

Osteopetrosis: A six month baby was referredfor evaluation of anemia. The baby had prominenteyes with searching nystagmus, beaked nose andabsence of filtrum of upper lip. There wasassociated hepatosplenomegaly. Peripheral smearrevealed many red cells in the form of tear dropcells, normoblasts, myelocytes, metamyelocytesand thrombocytopenia. This is charecteristic ofleucoerythroblastic reaction in marrowinfiltration disorders. Skeletal Xrays revealeddense bones which was suggestive ofOsteopetrosis. Pancytopenia is usually due toexcessive osteoid tissue in the marrow whichsuppresses the normal precursors.

Note: Other conditions causing myelothisicanemia include malignant infiltration orinflammatory granulomas in the marrow.

Fig. 4 Storage cell in Gaucher’s disease Fig. 5 Hypersegmented polymorph seen inmegaloblastic Anemia

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UPDATE OF COMPONENTTHERAPY IN PEDIATRICS

* Nitin Shah

Pediatric transfusions

Child is not a miniature adult and so anewborn is not a miniature child. The causes ofanemia and bleeding vary at different ages. Theindications, types and the dose of variouscomponents will accordingly vary dependingupon the age. The compensatory physiologicalmechanisms also differ at different age. Hencedecision as to when to transfuse, how much andhow fast to transfuse and what to transfuse willdepend upon the age and the weight of the child1,2.

Why not whole blood and whycomponents?

There are more than 6 important componentsin each unit of whole blood. Each component hasa specialized function. All these functions are notderanged in all the patients and hence all thecomponents are not required all the time. Bloodis always in short supply and making componentsfrom one unit of whole blood will satisfy theneeds of more than one patient from the sameunit of blood. Besides, giving whole blood willlead to harmful effects because of theunnecessary components infused resulting inplasma overload; lymphocytes mediatedtoxicities or allosensitization etc. Somecomponents can only be given effectively as

* Consultant Pediatrician,P.D. Hinduja National Hospital, MumbaiHon. Pediatrician, UHC,LTM General Hospital, Mumbai

component e.g. platelets, which are otherwisedestroyed in stored whole blood. Somecomponents are better given as component e.g.clotting factors, the levels of which can beachieved at much higher level or even 100% bygiving concentrates of such factors, than bygiving whole blood or even FFP.

Which components?

From one unit of whole blood, one can makepacked red blood cells, platelet pack (randomdonor platelets), granulocytes pack and freshplasma. Fresh plasma can be frozen at-30oC andused as FFP in future or pooled plasma can beconverted into components like cryoprecipitate,albumin, gamma globulins, anti-D globulins,plasma proteins etc. One can modify andmanipulate these components and get neocytepacks, frozen red cells, washed red cells orplatelets, filtered red cells or platelets, UV lightor gamma irradiated red cells or platelets. Onecan select a specific donor and get CMV negativeblood components, HLA matched bloodcomponents or blood products from specificminor blood group compatible donor. Lastly onecan get stem cells from the umbilical cord bloodof a newborn or peripheral blood of an older childfor autologous or allogenic bone marrowtransplant or rescue as the case may be.

Storage and shelf life

Whole blood is stored at 1-4oC. Shelf - lifewill depend upon the type of anticoagulant andadditive used. ACD is no more used. Blood storedin CPDA1 - A2 (Citrate phosphate dextroseadenine) can be kept for 35 days. Packed red cellscan be also stored up to 35 days with CPDA1.

HEMATO-ONCOLOGY


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Only saline washed red cells should be transferredwithin 24 hours of preparation. If one usesadditives like Nutrisol or Adsol, one can keep theblood for 42 days. Packed red blood cell is storedat 1-4oC and should be used within 24 hrsonce packed. Platelets are stored at 20-22oC andthat too on a constant agitator as resting plateletstend to aggregate. The shelf- life is 3 to 5 days.Granulocytes are kept at room temperature andshould be used within 24 hours of collection. FFPand cryoprecipitate have shelf life of one yearand should be kept at - 30oC. Frozen red bloodcells (with cryoprotective agents added to it) canbe kept at - 70oC and have shelf life of 5-7 years.

Whole blood

Whole blood is stored at 1-4oC and has ashelf life of 35 to 42 days as discussed before. Infirst 4-6 hrs of collection it has 100% of all thecomponents. As the time passes, changes occurin these constituents. Platelets fall to less than1% by 4-48 hrs. Labile clotting factors V andVIII also disappear in same time. Other clottingfactors like factor II, VII, IX, and X disappearthereafter. The potassium levels go up, ATPlevels fall and so do the levels of 2-3 DPG andpH, especially after 5-7 days of storage. Hencefor exchange transfusion, one should not usemore than 5-7 days old blood. 2-3-DPG levelstend to return to normal within 24 hrs oftransfusion.

Advantage of whole blood is that it containsall the components. Disadvantage is that it leadsto side effects due to plasma and lymphocytes,as their level remains almost 100% till last dateof storage. Besides, it is also a waste of othercomponents which are not required by therecipient.

Indications: Whole blood is naturally requiredwhere all the components of blood are necessaryto be replaced. This will occur during massibehemorrhage, cardiac surgery, exchange

transfusion especially in neonates and ECMO.For exchange transfusion it is better to use freshwhole blood as far as possible and definitely notmore than 5-7 days old. One can use reconstitutedwhole blood by using PRBC suspended in AB-ve plasma used with platelets if required. 10 cc/kg blood weight of whole blood will raise HCTby 5% and Hb by 1 to 1.5 gm%1,2.

Packed red blood cells (PRBC)

PRBC contains packed red cells in 22-50%of original plasma. It has nearly 100% ofpolymorphonuclear cells and lymphocytes as atthe time of collection but has less than 10%platelets and clotting factors. Ideal HCT forPRBC is 70-75% and it should not be too tightlypacked. For newborns, while doing exchangetransfusion, HCT can be adjusted to 50-55%using additional FFP or albumin.

Advantage of PRBC is that it is low volumeas compared to whole blood and hence does notlead to circulatory overload. It has less plasmaand hence has less citrate related toxicity It beingviscous, flows with difficult through pediatricIV lines. Other problem is that its shelf life is 24hrs, once packed. Lastly it contains significantamount of plasma and leukocytes to lead totoxicities related to them like allergic reactions,Non Hemolytic Febrile Transfusion Reaction(NHFTR), allosensitisation, GVHD, etc. 10cc/kgdosage body weight of PRBC will raise the HCTby 10% and Hb by 3-4 gm%.

Indications: It is used for replacement of volumeas well as oxygen carrying capacity. It is used inacute hemorrhage were more than 20% bloodvolume is lost, monitoring vitals, blood pressureand CVP. The commonest indication of PRBC ischronic transfusion dependent anemia as seen inthalassemias, sickle cell disease, congenitaldyserythropoietic anemia, Diamond BlackfanSyndrome, Fanconi’s anemia, aplastic anemia,chronic renal failure, cancer patients,

2003;5(1):15

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sideroblastic anemia etc. It is also useful inepisodic transfusions for acute hemolysis like inG6PD deficiency, malaria, autoimmune hemolyticanemia, etc. It is rarely, if at all, used in nutritionalanemia, if patient has severe anemia withimpending cardiac failure or has associatedcardio-respiratory disease. Lastly it can be usedbefore surgery, where patient is anemic with Hbless than 7 gm% and where moderate blood lossis expected during surgery. It is most oftenmisused as “top-up” in patients with nutritionalanemia, or before surgery to keep Hb above “10gm%”. In such cases, it is counterproductive asit can lead to immunosuppression of the recipientand delay in healing.

In newborn it is required for hemorrhageseen in cases of severe hemorrhagic disease ofnewborn, or any other cause of bleeding. It isused to replace iatrogenic blood loss, especiallyin sick preterms where more than one bloodvolume can be let out over the hospital stay forvarious diagnostic tests. For exchange transfusionone can use whole blood or reconstituted wholeblood as discussed before. PRBC is also usefulin anemia of prematurity when the baby has poorsucking, apneic spells, poor weight gain andanemia or less than 7 gm%. Very sick neonatesusually have associated sepsis, acidosis, DIC,bleeding and anemia and will need support withPRBC, platelets and FFP.

Precaustions

In patients who have chronic anemia andare transfusion dependent, special precautionsshould be taken. Detailed blood grouping shouldbe done before first transfusion to find outpresence of minor blood group incompatibility.Always use Coomb’s cross-matched blood todetect development of antibodies against minorblood group antigens. One should at least usewashed PRBC and if affordable, WBC filteredPRBC to decrease leuko-contamination.

Meticulous records of pre and post-transfusionHb should be kept to see for efficacy oftransfusions and suspect hypersplenism.Chelation should be started once serum ferritin ismore than 1000 ng/ml. Regular check up forplasma borne infections, serum ferritin levels andLFT should be done. Lastely, all these patientsshould receive hepatitis-B vaccine before theirfirst transfusion 3,4.

Platelet transfusions

Special requirements: Platelets have to be storedto 20 to 22oC on constant agitator. It should betransported quickly and infused rapidly over 20-30 minutes to prevent loss of platelets due toaggregation. No glassware should be used andonly plastic ware should be used to collect, storeand administer platelets. One should use ABO /Rh identical compatible donor. In emergency onecan use incompatible donors though the efficacymay be less than expected.

Types of Platelets: One an use either randomdonor platelets (RDP) or single donor platelets(SDP). One can also use manipulated plateletslike plasma-depleted platelets, washed platelets,WBC filtered platelets, UV or gamma irradiatedplatelets or platelets from a specific donor likeCMV negative donor or HLA matched donor.

RDP: It is also called as platelet pack and isderived from a single unit of whole blood. Itcontains 5-6 x 1010 platelets in 50-60 ml of plasmaper pack. One unit / 10 kg.body weight will raisethe platelet count by 20,000 to 30,000/cmm. Theadvantage of RDP is that it is less costly and easilyavailable from the blood bank shelf. Thedisadvantage of RDP is that it is less efficaciousthan SDP as it contains 6-7 times less number ofplatelets.Hence, more number of RDP packs areused exposing the recipient to more number ofdonors. Again one cannot use specific donors likeCMV negative or HLA matches donor whenrequired.


16

SDP: It is also called platelet concentrate and isobtained from a single donor by apharesis usingcell separator like COBECSPECTRA.Compatible donor is selected and subjected tocontinuous or discontinuous apharesis andplatelets are collected over 4-6 hrs. period. Itcontains 2-3 x 1011 platelets in 50-70 cc of plasma.It has 6-7 times more platelets than RDP. Thedonor should be healthy, off medicines likeaspirin and should have platelet count more than1.5 lakhs/mm3. After apharesis donor’s plateletcount can drop but sill will be above 1 lakh/ mm3.Advantage of SDP is that it is more concentratedand hence more effective exposing recipient toonly a single donor. One can use same donoragain after 2-3 weeks. One can select specificdonor like CMV negative or HLA matched donor.But it is extremely costly and needs sophisticatedequipments. Donor has to wait for longer periodin blood bank.

Criteria to transfuse: Platelet transfusions areusually given to those with thrombocytopenia dueto decreased production than to those withincreased destruction. Platelet transfusions aregiven when they have significant mucosal bleeds.Only skin bleeds do not warrant platelettransfusion, but such patients should be closelymonitored for any further mucosal bleeds5,6,7.

It is controversial as to when to giveprophylactic platelet transfusion. Child withthrombocytopenia usually does not bleedspontaneously unless the platelet count falls lessthan 50,000/mm3. The chances of intracranialhemorrhage increase when the count drops to lessthan 10-20,000/mm3. Decision when to transfuseis hence based on basic disease, type ofthrombocytopenia, platelet count, and presenceof associated coagulation abnormalities. A wellchild is given prophylactic transfusion when theplatelet count is less than 5,000-10,000/mm3. Asick child is given platelet transfusion when thecount is less than 10-20,000/mm3. Before surgery

it is given when the count is less than 30,000/mm3 and for surgeries in dangerous areas likeeye-ball, it should be given when the count fallsto 50,000/mm3. In patients with massivehemorrhage it should be given when the count isless than 30,000/mm3. as most of the circulatingplatelets are likely to be non-functional plateletsof the infused stored blood.

Indications: Platelet transfusions a given forthrombocytopenia or for platelet dysfunctionaldisorders.

1. Decreased platelet production: It occurswhen bone marrow failure occurs like in aplasticanemia, Fanconi’s anemia, TAR syndrome, andother constitutional hypoplastic anemia. It canoccur due to bone marrow infiltration e.g. inleukemias and other metastatic cancers. It canoccur following bone marrow suppression due tochemo-radio therapy or fulminant infections.Platelet transfusions have revolutionized thetratment and the outcome of pediatric cancers.The cause of mortality has shifted from bleedingto infections with better platelet support availablenow.

2. Increased consumption of platelets: Thisoccurs in DIC, NEC, HUS, TTP and Kasalbach-Merritt syndrome. In these cases, there is goodplatelet recovery at one hour after transfusion,but not at 24 hours. suggesting consumption.

3. Increased platelet destruction: This occursdue to immune or non-immune mechanisms.Immune destruction can occur in post-transfusionpurpura, autoimmune disease, ITP, andalloimmune disease of newborn. Non-immunedestruction can occur following drugs orinfections. Platelet transfusions are generally noteffective in this group of diseases, as they willbe immediately destroyed after transfusion.However, in life-threatening bleeding likeintracranial hemorrhage one may give platelet

2003;5(1):17

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packs just to tide over crisis till splenectomy isdone or IVIG is administered.

In alloimmune thrombocytopenia ofnewborn, mother is PLA-1 antigen negative andchild is PLA-1 antigen positive. This leads toallosensitization of the mother with productionof alloantibodies, which are passed to the babytransplacentally leading to immune destruction ofbaby’s platelets. Washed mother’s platelets aregiven to the baby in such cases.

4. Hypersplenism: Normally 1/3rd of plateletsare pooled in the spleen. This proportion willincrease in patients with hypersplenism due toany reason. Again platelet transfusions may notbe effective in such cases, as they will beimmediately removed from the circulation intothe enlarged spleen.

5. Dilutional: In patients with massivehemorrhage or following exchange transfusions,dilutional thrombocytopenia can occur whenmassive amount of whole blood are used in suchcases. Additional platelet transfusions may berequired in such cases.

6. Platelet-dysfunction: Various congenital andacquired platelet functional disorders may presentwith significant bleeding. If local measures failto control bleeding, platelet transfusions will berequired. One should use platelets sparingly insuch cases as allosensitization may prevent goodrecovery in future after a number of transfusionsare given. One can use HLA matched plateletsin such cases.

Platelet transfusion efficacy: One unit of RDPper 10 kg.body weight increases platelet countby 20,000 to 30,000/cmm. SDP is 5-7 times moreefficacious than RDP. The efficacy of platelettransfusion depend upon various factors. Plateletfactors like sources of platelets, type of platelets,storage, collection and administration will affectthe efficacy. Smililarly, factors in receipient that

affect the efficacy include pre-transfusion count,fever, sepsis, size of liver and spleen, presenceof antibodies or consumption coagulopathy anddrugs taken by the receipient.

Clinically one can judge the efficacy byseeing the cessation of bleeding. One can lookfor the expected increments by calculatingConsumption coagulopathy index (CCI) asfollows by doing platelet count at one hour and24 hrs. after transfusion.

Post tr. pl. ct - Pre-tr.plat.ct

Platelets infused x 1011

Post.tr.pl.ct : Post transfusion platelet CountPre-tr.pl.ct : Pre transfusion platelet CountCCI = Corrected count incrementBSA = Body surface area in m2.

Normal CCI is atleast 10,000 at one hour,and 7,500 at 24 hrs. If CCI is normal at one hour,but less at 24 hrs, it suggests consumptioncoagulopathy. If CCI is less at 1 hour itself, itsuggests immune destruction.

Granulocytes

People have logically tried giving granulocytetransfusion in patients with severe uncontrollableinfection, in patients with congenital or acquiredneutropenia or neutrophil dysfunction. It is usuallyreserved for neutropenic patients with fulminantsepsis not controlled by antibiotics and antifungalwith ANC < 300 in newborn, < 100 in infants and< 500 in immune compromised host. It shouldalways be used along with antibiotics andantifungals.

Granulocytes can be given by three ways.Granulocyte pack can be obtained from buffycoat. Though it is less costly, the cells becomenon-functional. It can be obtained by aphaeresisfrom a donor. The cells remain functional but it

CCI = ----------------------------------- x BSA m2


18

is costly. In newborns one can do partial exchangewith fresh whole blood to replace granulocytes.

The dose is 10o granulocytes/kg. body weightper dose. It can be repeated 12-24 hourly for 4-6days. Each pack of granulocyte has 1011

granulocytes in 200 cc of plasma. It is to be storedat room temperature and used within 24 hrs. Itobviously leads to all the side-effects related toplasma and lymphocytes. One should use ABO /Rh compatible donor.

Why leucodepletion?

Donor lymphocytes present in most of the bloodcomponents do not serve much purpose but canlead to major side effects. Antibodies can developagainst lymphocytes and platelets and lead tonon-hemolytic febrile transfusion reactions(NHFTR). Activated lymphocytes can releasecytokines like IL2, TNF during storage, whichcan also cause NHFTR. NHFTR is especially aproblem for patients needing recurrent bloodtransfusions. Lymphocytes lead toallosensitization and subsequent graft rejectionin prospective candidates for bone marrowtransplants. Lymphocytes bear intracellularpathogens and can transmit infections like HIV,HTVL, EBV, CMV etc. Lymphocytes can leadto pulmonary toxicities like ARDS. In surgicalpatients lymphocytes can lead to immunesuppression and delay healing. Lastly, in immune- compromised patients and in transfusion fromfirst degree relatives, it can lead to transfusionassociated graft Versus host disease (TAGVHD).Dose requried for NHFTR is > 5 x 106

lymphocytes whereas for TAGVHD it is > 107

cells/kg body weight. One pack of PRBC has 109

WBC, RDP has 4-6 x 107 WBC, SDP has 2-4 x108 WBC and granulocyte pack has 1011 WBCS.Hence all these components can lead to all theabove-mentioned lymphocyte mediatedtoxicities8,9. Ideally all the transfusion should beleuko-depleted especially in patients needing

recurrent transfusions and in immune-compromised hosts.

Methods of leucodepletion

There are various ways of leucodepletion.Each method has its own merits and demerits.

1. WBC filter: 3rd generation WBC filters arehighly efficient. The efficacy is 99.5 %. Theycontain fiber mesh to which the WBC stick andget filtered. When used during collection itselfthey will remove lymphocytes at source and henceprevent release of cytokines on storage. Theycan also be used at the bedside while transfusingthe blood. The advantage of WBC filter is its highefficacy and simplicity to use. The disadvantagesinclude its high cost and inability to preventTAGVHD. Each filter costs Rs. 600 - 700/- andis not re-usable. Ideally all transfusions should begiven using filters especially if patient needsrecurrent transfusions or develops NHFTR.

2. Washed cells: Washing with saline or bloodprocessor not only removes WBC but also plasma.The efficacy of WBC removal is 90% and thatfor plasma 99%. Hence it not only will reduceNHFTR, allosensitization and other toxicitiesrelated to WBC but will also reduce allergicreactions to plasma proteins. Preparation issimple. Disadvantages are that it is not veryeffective in leucodepletion and cannot preventTAGVHD. Besides it needs cold centrifuge toprepare washed cells. All red cell transfusionsshould be given using at least washed cells andpreferably with WBC filters in patients needingrecurrent transfusions and those with NHFTRor allergic reactions. Washed platelets frommother are given to a baby suffering fromalloimmune thrombocytopenia.

3) Gamma irradiation: TAGVHD can be onlyprevented by gamma irradiating the blood. It wasfound that doses up to 10000 cGy do not alter

2003;5(1):19

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RBC function and doses up to 5000 cGy do notalter platelet functions. Hence dosage of 2500 -3500 cGy are used to irradiate the components.One can use 137-cs insulator or 60 CO macine.The only disadvantage is need for thesophisticated irradiator and chances of membraneleak of the cells irradiated and increasedpotassium levels. Hence blood should beirradiated just before infusion or else supernatentplasma should be removed before transfusion.

Ideally all blood should be irradiated wherethere is risk of TAGVHD. This includestransfusion given to newborn especially preterms< 1200 gms, intra-uterine transfusion, patient withprimary or secondary immunodeficiency, cancerpatients, organ transplant recipients andtransfusion given to normal person from a firstdegree relative donor.

4) Frozen cells: RBC can be frozen at - 70oCand be kept for 5-7 years. While freezingcryopreservation with glycerol is done to preventintracellular ice formation. It should be thawedgradually and deglycerolized Once thawed shouldbe used within 24 hours. The efficacy forleucodepletion is 90% and plasma deplection is99%. Hence it reduces toxicities related to bothlymphocytes and plasma. Advantage of frozencells is its availability in emergency where onecan use O-ve frozen cells in AB negative plasma.One can collet blood from CMV negative donors,HlA matched donor or rare blood group donorsand freeze it for future use. Lastly autologousblood collected for surgery can be frozen and usedin future, if surgery gets postponed for somereasons. Disadvantage of frozen cells is that itneeds sophisticated instruments to prepare andstore and is extremely costly. It cannot preventTAGVHD.

Fresh Frozen Plasma (FFP)

Platelet poor plasma obtained at the end ofcentrifugation while making components is frozen

at - 30oC to make FFP. The shelf life of FFP isone year and it is stored at - 30oC. It should betransfused within 4 hours of thawing to roomtemperature. FFP contains all the plasma proteinsincluding albumin, gamma globulins and the mostimportant clotting factors. As labile factor V andVIII tend to decrease on storage, freezing of theplasma should be done within 4-6 hours ofcollection to prevent loss of these factors. Oneunit of FFP has 150 cc - 200 cc of plasma and 1ml.of plasma contains approximately 1 unit ofeach clotting factor. One can use 10-15 cc/kg.body weight of FFP given every 12 hourly. Henceone cannot raise the factor leves beyond a certainlimit without leading to volume overload.

FFP is often misused as a volume expander.As FFP contains plasma, it can lead to allergicreactions, anaphylaxis in IgA deficient patient andcan transmit all the plasma borne infections.Hence, albumin should be used as a volumeexpander as it is much safer. Similarly albuminand not FFP should be used to replace proteinsor albumin. If patient needs both volumeexpansion as well as clotting factors like in DIC,sepsis, NEC etc. one can use FFP.

FFP is mainly used to replace clotthingfactors. It can be given when the patient presentswith bleeding for the first time where thediagnosis is uncertain as to which factor isdeficient. In known cases of hemophilia, it is betterto use factor concentrates, as they are moreefficient and safe. FFP is used for deficienciesof other factors like factor V, VII etc. wherefactor concentrates ae not available. It is alsoused where multiple factors need to be replacedas in case of hemorrhagic disease of newborn,liver disease, preterm with liver dysfunction, DIC,etc. FFP also contains AT III< protein C andprotein S and hence is useful in the deficiency ofthese factors too. It is used for plasma exchangein patients with TTP. It can be used to reconstitutewhole blood along with PRBC or to adjust


20

hematocrit of PRBC for exchange transfusion innewborn. Lastely, FFP is useful to prevent andtreat coagulopathy due to L-asperagenase incancer patients.

FFP leads to all the side effects related toplasma like allergic reactions like urticaria,anaphylaxis in IgA deficient patient andtransmission of plasma borne infections to therecipient. In small babies, it can lead to hemolysisif it contains high levels of antibodies againstrecipient’s blood group antigens.

References

1. Shah Nitin, Lokeshwar MR. Blood componentsin pediatric practice. Proceedings of SouthPedicon 2000; pp. 47-59.

2. Strauss RG, Levy GJ, Sotelo-Avila c et al.National survey of Neonatal TransfusionPractices; II. Blood Component therapy.Pediatrics 1993; 91: 530-536.

3. Voak D, Cann R, Finney RD et al. Guidelines foradministration of blood product transfusion ofinfants and neomates. British Committee forStandards in Hematology Blood TransfusionTask Force. Transfusion Medicine 1994; 4:1411-1413.

4. Ennio CR. Red cell Transfusion Therapy inChronic anemia. H/OCNA 1994; 8: 1045-1052.

5. Consensus Conference of Platelet Transfusion.Br J Cancer 1998; 78: 290-291.

6. Beulter E. Platelet transfusion: the 20000/L trig-ger. Blood 1993; 81: 1411-1413.

7. Rentels PB, Kenney RM, Crowley JP. Therapeu-tic support of the patient with Thrombocy tope-nia. H/OCNA 1994; 8:1131-1151.

8. Rosen NR, Weidner JG, Boltd HD et al. Pre-vention of Transfusion associated graft-versus-host disease: selection of sufficient dose ofgamma irradiation. Transfusion 1993; 33:125.

9. Miller JP, Mintz PD. The use of Leucocyte-Reduced Blood Components H/OCNA 1995;9:69-90.

NEWS AND NOTES

XIII CONGRESS OFTHE INTERNATIONAL PEDIATRIC NEPHROLOGY ASSOCIATION

Date: 29th August - 2nd September, 2004

Venue: Adelaide Convention Centre, Adelaide, Austria

Contact:

IPNA 2004 Congress ManagementPO Box 20, Kent Town SA 5071Australia

Phone : + 61 8 8363 4399Fascimile : +61 8 8363 4577Email : [email protected] : www.ipna.2004.com

2003;5(1):21

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AN APPROACH TO A CHILDWITH RECURRENT BLEEDING

* Revathi Raj

As early as the eighteenth century, Hebrewlaw in Bologna stated that if two sons of the samemother died of uncontrollable bleeding followingcircumcision, subsequent offspring were notcircumcised.

To evaluate a child with excessive orrecurrent bleeding, an understanding of basicclotting mechanisms is necessary. The bloodcirculates in a fluid phase that is controlledthrough a series of coagulation proteins that arebalanced by natural inhibitors. Once a bloodvessel is injured, the vessel contracts, andplatelets adhere to the site. The platelets thenundergo the aggregation and release reaction thatis triggered by exposure to sub-endothelialcollagen. A series of changes in the plateletsproduces a platelet plug. The plasma coagulationsystem is then activated to form fibrin, the finalresult of the haemostatic mechanism.

The history is extremely important inevaluating children with disorders ofhaemostasis. Children with severe haemostaticdefects often have repeated episodes of bleedingthat occur without apparent cause, or severebleeding in response to relatively minor stimuli.Spontaneous bruising or petechiae, excessivebleeding after a dental extraction, a surgicalwound or an accidential laceration point towardsa bleeding tendency. Excessive bleeding during

* Consultant in Pediatric Hematology and Bonemarrow TransplantationApollo Hospitals, Chennai

menstruation may be the first presentation of ableeding diathesis.

Since many of these disorders are inherited,the family history is crucial. The family history ofchildren with factor VIII or factor IX deficiencyshows the characteristic pattern of sexlinkedinheritance. However, about a third ofhaemophilic patients are spontaneous mutationswith no family history and sometimes X linkeddisorders may skip generations. Von Willebranddisease and dysfibrinogenaemia are usuallyautosomal dominant. All other coagulation factordefects are autosomal recessive. Platelet functiondisorders are usually autosomal recessive apartfrom Wiskott Aldrich syndrome which is inheritedas X linked recessive.

Physical examination of children withhaemorrhagic disorders involves evaluation ofthe type of bleeding (petechiae, ecchymoses,haematoma, haemarthrosis or mucous membranebleeding). The characteristic bleedingmanifestation in a patient with a vascular orplatelet defect are skin and mucous membranebleeding. The typical bleeding signs in a patientwith a defective coagulation system are deepbleeding into joints and muscles, large spreadingecchymotic lesions and haematomas.Examination must include looking fordysmorphic features to suggest Fanconi anaemiaor partial albinism associated with platelet typebleeding.

The usual lab screening tests for a patientwith a suspected haemostatic defect includeplatelet count, bleeding time, prothrombin time,activated partial thromboplastin time and thrombintime. The whole blood clotting time is

HEMATO-ONCOLOGY


22

prolonged only when factor VIII is less than 1%and hence is an insensitive screening test. AnAPTT on the other hand is abnormal when factorVIII is done to 30%. (Fig 1). Bleeding time givesan accurate estimate of vascular integrity andplatelet function provided it is standardised.

A child with extensive scarring from smallsuperficial wounds and a prolonged bleeding timeis most likely to have Ehlers Danlos syndrome.A child with a prolonged bleeding time with largeplatelets on smear could have Glanzmann’sthrombasthenia and a child with eczema,recurrent rectal bleeding, prolonged bleedingtime with small platelets on smear could haveWiskott Aldrich syndrome (Fig.2).

Automated cell counters estimate meanplatelet volumes accurately and will give a clueregarding platelet size. Formal plateletaggregation studies will help to arrive at adiagnosis in children with a history of platelettype bleeding and a prolonged bleeding time.However, these tests require a significant volume

of blood to separate platelet rich plasma and wemay have to wait until the child is a little older.The recent introduction of an automated plateletfunction analyzer (PFA 100) has revolutionizedscreening for platelet disorders. The analyzerrequires only small volumes of whole blood toassess platelet function.

Isolated prologation of PT is suggestive offactor VII deficiency, Whilst a prolonged APTTis suggestive of factor VIII, IX, XI or XIIdeficiency. When both PT and APTT areprolonged, Von Willebrand disease, factor X,V, IIor fibrinogen deficiency should be suspected.When all haemostatic screen results are normalwith a significant bleeding history, then a FactorXIII screen is indicated (Fig. 3).

Once the diagnosis is established, allchildren with recurrent bleeding problems shouldbe managed along these broad principles. Theyshould be vaccinated against hepatitis A and Bviruses and be issued a card with ther diagnosisand blood group on the same. The physician

2003;5(1):23

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Mucus Membrane BleedingPetechiae and / or

Small Ecchymoses of skinPlatelet Count

Reduced NormalBone Marrow Bleeding Time

MKC - Normal or MKC - Reduced Prolonged Normal↓ ↓ ↓ ↓

Accerated Destruction Deficient Platelet Dysfunction Blood Vesselor abnormal pooling Production DiseasesImmuneInfectionsDICHypersplenismIdiopathicHereditary FormsCongenital Heart DiseaseVeous ThrombosisPNH

LeukemiaToxinsDrugsNutritionalInfiltrative DiseaseHereditary FormsCongenital Heart DiseaseMyelofibrosisAnoresia Nervosa

DrugsUremiaLiver Failurevon Willeband DiseaseHereditary FormsCongenital Heart Disease

VasculitisScurvyHereditary

HamorrhagicTelanglectasia

Schonlein HenochPurpura

Fig 2. Workup of a patient with a defect in the primary hemostatic mechanism

Large EcchymosisHematomaHamarthrosis

Partial Thromboplastin time (PTT)Prothrombin Time (PT)

PTT - Prolonged PTT - Normal PTT - Prolonged PTT - NormalPT - Normal PT - Prolonged PT - Prolonged PT - Normal

Thrombin Time (TT)

TT - Prolonged TT - Normal

Hemophillas Factor VII Afibrinogenemia Liver Disease Factor XIIIv Wd Deficiency Dysfibrinogenemia Vitamin K. Deficiency DeficiencyCirculating DIC Warfarin α2 AntipasminAnticoagulant Liver Disease Deficiences DeficiencyHeparin Heparin in II, V or X

DIC (early)CirculatingAnticoagulantDysprothrombinemia

↓ ↓

Fig 3. Workup of a patient with a defect in the secondary hemostatic mechanism


24

caring for the child should educated the familyregarding avoiding aspirin, NSAIDs, IMinjections, contact sports and head injury. Geneticcounseling should also be provided, as the burdenof caring from more than one child with a bleedingproblem is high, both in terms of financial andemotional aspects. A lead clinician who isavailable at all times to provide advice andsupportive care makes a big difference in not onlyarresting bleeds but also prevention ofdeformities.

Finally, both the physician and the familymust be aware of the infectious complicationsassociated with frequent use of blood products.

Platelets, fresh frozen plasma and cryoprecipitateshould be used judiciously as and when required.If there are no financial constraints, the use ofvirally inactivated factor concentrates orrecombinant factor concentrates can be used asand when appropriate. Gene replacement therapyhas been tried in factor IX deficiency and hasbeen successful. Liver transplantation offers achance of cure for defects of secondaryhaemostatic mechanisms. Recombinant factorVIIa seems to be a promising agent that helpscontrol bleeding in all defects of the coagulationpathway, but the tremendous cost precludes itswidespread use at present.

NEWS AND NOTES

INDO-UK SYMPOSIUM ON HOT TOPICS IN PEDIATRICS

1-2 February, 2003

Under the auspices ofIndian Academy of pediatrics

&Royal College of Pediatrics and Child Health (RCPCH)

Host : Indian PediatricsSupported by : Ministry of Health & Famil Welfare, British Council,

IAP Delhi, MCI, DST, ICMRVenue : Banquet Hall, Ashok Hotel, Chanakyapuri, New Delhi

Registration Fee *Upto 15th January, 2003 Rs. 1200/-After 15th January, 2003 Rs. 1500/-

* Cheque / DD to be drawn in favour of ‘Indian Pediatrics Symposium’

Mail to:Dr. Panna ChaudhuryOrganising Secretary, Department of Pediatrics,Maulana Azad Medical College, New Delhi - 110 002.Tel: 011 - 23236031, 26252265, 011-24674211 (R)E-mail: [email protected] / [email protected]

2003;5(1):25

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MANAGEMENT OFIMMUNOCOMPROMIZEDCHILDREN WITH CANCERS -ROLE OF THE PRIMARY CAREPHYSICIAN

* Saradha A. Sarnaik

Introduction

Patients who are being treated for cancerhave a predisposition to a variety of infectiouscomplications because of abnormal host defensemechanisms. Normal host defense mechanismsinclude firstly, an intact surface skin and mucousmembranes in the mouth and GI tract that act asa mechanical barrier to invasion withmicroorganisms. A second defense areneutrophils and monocytes that can migrate,phagocytose and kill invading microorganisms.Thirdly cell-meditated immunity that is conferredby lymphocytes (T & B cells) results in asecretion of specific antibody that participates inlysis of invading organisms.

Pathophysiology

Patients who are being treated withchemotherapy and/or radiation often developpainful mucositis, with mucosal ulceration in themouth, esophagus and the entire GI tract. Thus,the first physical barrier to microorganisms isdisrupted, nutrition is interfered with because ofpoor feeding from mouth pain and problems with

* Attening Hematologist/Oncologist,Children’s Hospital of Michigan, andProfessor of Pediatrics,Wayne State University School of Medicine,Detroit, Michigan, USA

swallowing. The resultant abnormal nutrition is acontributing factor to increased difficulty withfighting infections.

Almost all cancer chemotherapeutic agentscause neutropenia (vincristine, steroids, andasparaginase do not usually produceneutropenia). Thus, a second important barrierto infection is lost in patients being treated formalignancy. The severity, duration and timingof neutropenia depend on the particular drugsused and their dosage. The usual nadir is between10 and 14 days after administration, with recoveryto baseline by day 21. Anemia andthrombotytopenia usually accompany lowneutrophil counts and contribute to an increasedsusceptibility to infectious complications. Whileneutropenia is defined as absolute neutrophilcount (ANC) < 1500/mm3 the risk of infectionincreases when PMNs drops to < 1000/mm3.Modern, more aggressive treatment protocols,withhold therapy when patients have ANCbetween 500 - 750/mm3. Profound neutropenia(ANC<100) has a high risk of serious infections.Also, neutropenia lasting longer than 7 days isassociated with multiple and severe infections.

Defective cell mediated immunity isassociated with steroid use. Steroids are a majoragent in the treatmetn of ALL. Otherchemotherapeutic agents such as methotrexate,6-mercaptopurine and cyclophosphamide alsoimpair CMI, probably by causing lysis oflymphocytes as well as interfering withlymphocyte function. Splenectomized patients orthose rendered functionally asplenic byirradiation of the spleen have problems withhumoral immune responses.

HEMATO-ONCOLOGY


26

Management of patients with immuno-compromized states: practical considerations.

Monitoring of CBC

Weekly CBCs are usually performed tomonitor the need of transfusion of RBC or plateletconcentrates as needed to support the patient.RBC transfusions are given to maintainhemoglobin levels >7gm%, platelets are generallyinfused for gross bleeding, particularly frommucous membranes (epistaxis, gum bleeding),spontaneous severe bleeding is not usual withcounts > 20,000/cubic mm3. Thus, in a non-bleeding child, platelet transfusion may be usedfor counts of 15,000/cmm or less.

Dietary considerations

As previously discussed, children withcancer are at risk for malnutrition, particularlythose who have sub-optimal nutritional statusbefore treatment is begun. Factors that contributeto poor nutrition include mechanical obstructionfrom the tumor itself, increased metabolic andcaloric needs from tumor growth, ileus anddelayed gastric emptying from surgery,chemotherapy and/or radiation treatment alsoworsen weight loss.

The task force of the Americal Academyof Pediatrics has published criteria for nutritionalintervention. Criteria include weight loss of >5%of the pre-illness weight, low weight for height,or serum albumin level <3.2gm/dl. Nutritionalintervention should focus on caloric dense foods.If financially feasible, commercially availablesupplements should be used. If acceptance orcost are barriers, favorite high caloric foodsshould be offered. Frequent small feeds (6 to 8times a day) and bland and cold foods if thereare mouth sores are often more acceptable tochildren. Tube feedings should only be used ifthe neutrophil and platelet counts are not low,because trauma from passing the tube and

infectious complications from aspiration can bea risk in such patients. Finally, if feasible andnecessary, parenteral nutrition by central linecatheters can be used. Patients who have severeneutropenia should best avoid raw foods (rawfruits and vegetables) because despite washingthese foods carry the risk of ingestion andcolonization of molds or other infectiousorganisms. Cooked foods are more likely to besterile.

If chemotherapy-related nausea andvomiting is a problem, giving a dose of anantiemetic just prior to meals is a good parctice.Parents should be encouraged to remain positiveand should be given supportive guidance, becausechildren may request a food item, only to refuseit after a bite or two, and can be perceived to be“difficult”. Actually, this behavior is because oftherapy-related hypoguesia or abnormal taste andsmell sensation. Experimentation with texture anddifferent added condiments may be helpful.

Isolation procedures

It is not feasible (nor indicated) tocompletely isolate children for fear of contagiousexposure during immunosuppressive therapy.The most over-looked and very simple precautionof good hand washing when taking care of thechild is both important and inexpensive. Whilecontact with peers or others who have infectionsis often anxiety-provoking to parents, only anexposure to varicella is of particular importanceto the management of immunosuppressedchildren. The period of infectivity for varicellais 48 hours before appearance of the eruption andfor 6 days after the last new lesion appears.Patients who are exposure to an infectious personshould receive passive immunization with zosterimmune globulin within 72 hours of the exposure.Acyclovir should be given if varicella occurs inan immunosuppressed child. The intravenousroute is preferred. Data from studies in India point

2003;5(1):27

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out to the efficacy of oral acyclovir in thissituation. (20 mg/kg/does four times a day for5 days)

Pneumocystis prophylaxis

Children undergoing chemotherapy areprone to pneumocystis carinii infections that arepotentially life-threatening. They should thusreceive oral trimethorprim and sulphamethoxazolecombination as prophylaxis (75mg/M2 oftrimethorprim) twice daily on 3 consecutive daysa week while they are on chemotherapy.

Management of fungalcolonization

Colonization with candida (thrush) can becontrolled by oral topical mycostatin, 1 cc fourtimes a day for the duration of expectedneutropenia.

Management of febrile episodes

History: History should be obtained, particularlyregarding the chemotherapeutic drugs used, homemedications, (including steroid use) prophylacticantibiotics, recent antibiotic administration. thestatus of the malignancy (remission of relapse),most recent blood counts. Presenting complaintsare important, particularly cough, abdominalpain, ongoing fluid losses from diarrhoea orvomiting, exposure to infectious agents.

Physical examination: The vital signs,particularly the respiratory rate and presence ofrespiratory distress or hypotension, rashes,petechiae or bruising, paronychia, infections atsites of skin puncture (finger sticks, venepuncturesites, catheter sites). Potential sites for infectionsinclude the teeth and gums, sinuses, abdomen fortyphlitis (right lower quadrant pain and/ortenderness, a sign of caecal inflammation andpotential for bowel rupture in neutropenicpatients). The perirectal area should be inspectedand palpated for tenderness or erythsema. A rectal

examination (or rectal temperature) should beavoided in a neutropenic patient, particularly withthrombocytopenia, as the trauma itself can setup a parirectal infection.

Laboratory investigation: As a minimum, aCBC, blood culture from a peripheral vein as wellas a central line if present should be obtained.Urine culture should also be obtained. Otherinvestigations should be done if clinicallyindicated. These include liver and kidney functiontests and chest X-Ray if pneumonia is suspected.Thick and thin smears for malarial parasites,testing for dengue fever should be done if theseinfections are suspected.

Antibiotic choices - a) If patients are notneutropenic and do not have an indwelling centralline, empiric treatment with a single antibiotic suchas a third generation cephalosporin to cover grampositive and gram negative organisms aftercultures are obtained is a good treatment plan.

b) Patients with an indwelling catheter,should be treated with oxacillin and anaminoglycoside regardless of whether they areneutropenic or not.

c) For patients with neutropenia and noindwelling catheter, oxacillin and anaminoglycoside can be used.

d) For patients with neutropenia and anindwelling catheter, vancomycin and gentamicinshould be used.

Recent studies favor the use of monotherapywith agents such as ceftazidime in patients whodo not have an indwelling catheter.

Systemic antifungals - It is recognized thatpatients with prolonged profound neuropenia areat risk for deep seated fungal infections withorganisms such as aspergillus. There is a growingpractice to treat such patients with systemicparenteral antifungal agents such as amphotericin


28

B. Patients with more than 7 days of persistentfebrile neutropenia are candidates for suchtherapy. Newer agents such as the liposomalformulations of amphotericin are less toxic butmore expensive. Voriconazole and casperfunginare newly released agents in the US for difficultto treat severe fungal infections.

Viral Infections- Disseminated varicella-zosterinfections are amenable to treatment withacyclovir. CMV and herpes simplex infectionscan likeweise be treated with gancyclovir. Thus,it is of some importance to establish the presenceof these infections by appropriate laboratoryinvestigations, if these are available.

Bibliography

1. Infectious complications in the pediatric cancerpatient. In Principles and Practice ofPediatricOncology, 3rd edition, editors: PhilipPizzo and David Poplack, Lippincott-Ravenpublishers, 1997.

2. Jain Y, Lodha R et al. Oral acyclovir in VaricellaZoster Virus Infections in Children with AcuteLymphoblastic Leukemia. Indian Pediatrs2000; 37: 1239-1241.

3. Acute Lymphoblastic Leukemia. In Nathan andOski’s Hematology if Infancy and Childhood,5th edition, Volume 2, Editors: David Nathanand Stuart Orkin. W.B Saunders Companypublishers, 1998.

NEWS AND NOTES

February 8 and 16, 2003

Oncology - Hematology 2003Contact:

Dr. Purvish M. Parikh, Program Director,Room No. 33,Tata Memorial Hospital, Parel,Mumbai 400 012.

Tel. 022 4177213; Fax 022 4154005E-mail : oncology [email protected]

February 23, 2003

CME on Common Renal Disorders, Chandigarh

Contact:

Dr. J.S. Goraya, Organising Secretary,Department of Pediatrics,Govt. Medical College,Chandigarh 160047.

Tel. 0172 665253-59 ext. 2503 (O)0172 616128 (R)E-mail : [email protected]

2003;5(1):29

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COMPLETE BLOOD COUNTSIN PEDIATRIC PRACTICE

* Ganthimathy Sekhar

The modern era of hematology began in theearly 1900s. Ever since, this field has flourishedand the knowledge and understanding is everexpanding and ever accelerating. Severallaboratory tests form the backbone of diagnostichematology, the most important being thecomplete blood count or hemogram.

The complete blood count (CBC) is a simpleand inexpensive test, which is relatively easy toorder the interpret. However it should be carefullyanalyzed, based on the knowledge of themethodologies used and the pitfalls in these.However it can still give valuable clues todiagnosis of disease states.

Over the years the components of the CBChave expanded with the introduction ofincreasingly sophisticated instruments. The basicparameters are:

Hemoglobin

Hematocrit

Total red cell count (RBC count)

Red cell indices - MCV (mean corpuscularvolume), MCH (mean corpuscular hemoglobin),MCHC (mean corpuscular hemoglobinconcentration) and RDW (red cell distributionwidth).

Total white cell count (WBC count)

Differential WBC count (Diff. count)

Platelet count

By convention the Peripheral blood smearexamination is done as part of the CBC. In somecentres the reticulocyte count is also done as partof the CBC.

‘Correct collection of blood specimens is thecornerstone of accurate diagnosis in PediatricHematology’ and nowhere is this more felt thanis estimating CBCs. Free flowing blood, correctvolume of blood to anticoagulant, collection froma correct site (avoid IV lines) and avoidance ofsqueezing of the site are all crucial factorsaffecting the outcome of test results. The idealanticoagulant is EDTA in the concentration of 1to 2 mg per ml of blood. (EDTA should bepreferably in a powdered form, for which usageof vacutainers give more accurate results).

Methods of determination of CBC

CBC estimations may be done manually orby authomated hematology analyzers.

Manual counts: Manual methods are more idealfor measuring single parameter and calibratingparameters like hemoglobin and hematocrit.

Automated analyzers : These increase theaccuracy and speed of analysis. However theautomated instruments have to be regularlycalibrated using reference methods and thereproducibility frequently measured. Ideally thecalibration settings are checked at the time ofinstallation of a new machine, at the time of anyequipment malfunction or monthly intervals.

HEMATO-ONCOLOGY

* Consultant Clinical PatholgistKanchi Kamakoti CHILDS Hospital,Chennai - 600 034.


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Commercial controls with known values shouldbe run everyday to check the performance of themachine. However these machines are estimatedto have a false ‘flagging’ rate of about 10 to 25% of patient samples. requiring a blood smearexamination.

Hemoglobin (Hb)

Hemoglobin estimation is done on any childwith symptoms or signs of anemia where thehemoglobin levels are below the reference range.Polycythemia is present with the Hb levels areincreased. The unit of measurement (UOM) isg/L (g/dl).

In most automated systems, Hb is measuredas cyanmethemoglobin by absorbancespectrophotometry. This relies on complete lysisof the RBCs and reliably measures all thehemoglobin variants except sulfhemoglobin.Some instruments now include sulfhemoglobinin the total hemoglobin measurement.

Hematocrit (Packed cell volume,PCV, Hct)

Hematocrit is the volume of the red cells ascompared to the volume of the whole bloodsample. Estimation of this parameter is used inthe diagnosis of anemia and polycythemia. Itshould be kept in mind that hemoconcentrationdue to various causes can affect the true levels.Both manual and automated methods can beused. On the automated systems these arecalculated as MCV multiplied by the red cellcount. In manual methods a timed application of

centrifugal force on a column of blood is done.However manual methods are preferred inpolycythemia and when these is abnormal plasmaoncotic pressure. Hematocrit estimation is alsoaffected by alteration of RBC shape. Hematocritsare conventionally reported as a percentage. (%).In SI units it is expressed as 1/1. eg. hematocritof 35% will be 0.35 1/1.

Red cell count

This is the measure of the number of RBCsin a unit volume of blood, the present UOM beingRBCs x 1012/L. As manual methods ofestimating RBC count are quite inaccurate, theywere not used much. With the advent of accuratecounting by automated analyzers they are nowbeing utilized more in the diagnosis of anemiaand calculation of the RBC indices. It is also usefulin roughly correlating hemoglobin levelsand hematocrit levels.

Correlations of hemoglobin with hematocritand RBC count

RBC count x 3 = Hemoglobin

Hemoglobin x 3 = Hematocrit.

However this is affected by many artifactualchanges which are detailed later.

Red cell indices

These include the MCV (mean corpuscularvolume), MCH (mean corpuscular hemoglobin),MCHC (mean corpuscular hemoglobinconcentration) and RDW (red cell distribution

Table 1. Definition of anemia based on hemoglobin and hematocrit

Age Hemoglobin Hematocrit

6 mos - 4 yrs < 11.0 g/dl < 33.0%4 years - puberty < 11.5 g/dl < 34.5%Postpubertal males < 14.0 g/dl < 42.5%Postpubertal females < 12.0 g/dl < 36.0%

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width). Used in the classification of anemias(Tables, 1 and 2) and hence gives clues to thepossible etiology. The reference ranges for thevarious age groups are mentioned later.

MCV : This is the average volume of thered blood cell and is measured directly inautomated counters. Manual calculation is asfollows:

Hematocrit (1/1)------------------------------------- x 1000Red cell count (x 1012/L)

The UOM is femtolitres (fl).

MCH: This is a measure of the hemoglobincontent per red cell. In automated counters this

is computed using the measurements of each redcell. Manual calculation formula is:

Hemoglobin (g/dl)------------------------------------- x 10

Red cell count (x 1012/L)

The UOM is picograms (pg)

MCHC: This is the average concentration ofhemoglobin per red cell and may be calculatedby the formula:

Hemoglobin (g/dl)------------------------------- x 100

Hematocrit (L/L)

The UOM is g/dl or %

Table 2. Classification of anemia based on MCV and RDW

RDW

MCV NORMAL HIGH

Low Thalassemia, chronic infections, Iron deficiency anemia,sideroblastic anemia

Normal Anemia of chronic disease, Early iron deficiency anemiapost hemorrhagic anemia,hereditary hemolytic anemias,red cell aplasiabone marrow replacement

High Reticulocytosis Megaloblastic anemia (Fig.3)Immune hemolytic anemias

Fig. 1 Microcytic hypochronic anemia(peripheral blood smear (PS)

Fig. 2 Normocytic, normochromic anemia(peripheral blood smear)


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RDW : This measurement is the coefficientof variation of the mean corpuscular volumedistribution expressed as a percentage. In otherwords it reflects the range of red cell sizes oranisocytosis measured within a sample.

Standard deviationRDW = x 100

mean MCV

In normal individuals the RDW from mostautomated instruments in about 11.5 to 14%4.

Classification of anemia based onMCV

If the MCV is less than 80 fl = microcytic (Fig.1)

If MCV ranges from 80 to 100 fl = normocytic(Fig. 2)

If MCV is more than 80 fl = macrocytic

If MCHC is less than 31g/dl and or MCH is27pg = hypochromia

Reticulocyte count

This parameter is the traditional measure ofRBC production and is usually expressed as apercentage of circulating RBCs. However thismeasurement is affected by the lifespan of thereticulocytes in circulation and by anemia(hematocrit). Hence the reticulocyte productionindex (RPI) which corrects for both is a more

reliable measure of RBC production. Reticulocyteproduction index is a measurement which convertsreticulocyte count (%) to an index reflectingproduction with corrections being made for1. Degree of anaemia 2. Early release ofreticulocytes from the marrow. The calculationis as follows :

Reticulocyte % Patients hematocrit (l/l)

Retic. maturation Normal hematocrit (l/l)time in days (RMT)

RMT is 1.0 day when hematocrit is 0.45 l/l,2.0 days at 0.25 l/l, and 2.5 days at 0.15 l/l. eg. ifhematocrit is 0.25 l/l and retic count is 20% then

20 0.25RPI x = 5.5

2.0 0.45

Normal RPI is 1 wherein the reticulocyte% is 1, the RMT is 1 day, hematocrit value of theindividual is the same as the normal hematocrit.

If the RPI exceeds 3, production of red cellsis increased and anemia is due to hemolyticanemia. If RPI is less than 2 a defect inproduction of red cells (bone marrow failure) ispresumed to be the cause of anemia. This anemiacould also be due to ineffective erythropoiesis(megaloblastic anemia, thalassemia). To furtherdifferentiate between anemia due to bone marrowfailure and ineffective erythropoiesis, somecentres do measurement of serum transferrinreceptors to TfR, TfR is elevated in ineffectiveerythropoiesis and is reduced in bone marrowfailure.

Points to remember whileinterpreting CBCs with RBCindices

1. In children less than 3 years, MCV is usuallylower than 80 fl and at times may even bearound 75 fl.

Fig. 3 Megaloblastic anemia (Bone marrowsmear)

x

2003;5(1):33

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2. The first hematologic manifestation of irondeficiency in children is an increase in theRDW.

3. RDW is increased in iron deficiency anemiaand normal in thalassemia. (both microcytic,hypochromic anemias)

4. MCHC is increased in hereditaryspherocytosis.

5. Errors due to inherent problems while usingautomated instruments, in certain clinicalconditions, should be kept in mind.

While blood cell count (TC) anddifferential count (DC)

White cells are counted after dilution in adiluent that lyses the RBCs both in the manualmethod and in automated machines. Automatedmethods of differential counting include a flowthrough system that identifies cells on the basisof cell size and staining characteristics.

A good, well stained, peripheral blood smearis however more useful as along with thedifferential count morphological changes in theWBCs can be studied simultaneously.

The UOM for the WBC count is x 109/Land % for the differential count. Both theseparameters are used most often to support thediagnosis of infections either bacterial or viral.

For example: In children aged 3 to 36 months(febrile, sick child) the total WBC count correlateswith the presence of bacteremia.

Fig. 4 Acute lymphoblastic leukemia (PS)

Table 3. Hematologic scoring system for the early diagnosis of neonatalsepsis

Parameter Finding Score

Total WBC count less than 5000 1more than 25000 at birth 1more than 30000 at 12 to 24 hours 1more than 21000 at day 2 onwards 1

Total neutrophil count No mature neutrophils seen 2Increased or decreased 1

Immature neutrophil count Increased 1Immature : Total neutrophil count Increased 1Immature Mature neutrophil count more than or equal to 0.3 1Platelet count less than or equal to 1.5 lakhs per cubicmm 1Degenerative changes in the more than 3 + for vauolation, toxic changesneutrophils or Dohle bodies 1


34

When the total WBC count is

- more than 15,000 there is 16% incidence ofbacteremia



In bacterial infections there is usuallyneutrophilia, with increased band or stab forms,and morphological changes like toxic granules,vacuolization and Dohle bodies in the cytoplasmof the neutrophils. In viral infections and entericfever there is usually a reduced total count or

leucopenia. Lymphocytes are seen increased inviral infections, tuberculosis and pertussis,Eosinophils are increased in parasitic infestationsand allergic disorders. In severe sepsis they arereduced in number. Monocytes are increased inconditions like malaria, kala azar, and viralinfections. Basophils are increased inmyeloproliferative disorders. Haemotologicalmalignancies like leukemias are diagnosed bydoing the TC and DC.

Platelet count

The normal range is usually about 1.5 to 3.5or 4 lakhs / mm3. Reduced platelet count orthrombocytopenia is when the platelet count is

Table 4. Some sources of error* in estimating complete blood counts

1. Cold agglutinins seen in infectious monomucleosis ↓ RBC countand mycoplasma pneumonia ↑ MCV

↑ MCH

2. Fragmented RBCs and seen in disseminated intravascular ↓ RBC countvery small RBCs coagulation, hemolytic conditions, ↑ Platelet count

severe microcytosis

3. Platelet clumps seen when there are small fibrin ↓ Platelet countPlatelet satellitosis clots in the blood sample and

some EDTA samples

4. Giant platelets seen in reactive conditions and in ↑ RBC countplatelet function disorders

5. Nucleated red cells seen increased in many conditions, ↑ WBC countare counted as WBCs

6. High blood glucose Hyperosmolar plasma causes ↑ MCVlevels (400-600) uremia cell swelling ↑ Hct

7. Very high WBC counts when WBC count is more than ↑ Hb50,000 / cumm ↑ Hct

↑ MCV↑ RBC count

* The above can be checked by a careful scrutiny of the peripheral blood smear and otherappropriate investigations

2003;5(1):35

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Table 5. Pediatric reference ranges for commonly used red cell parameters

Age Hb g/dl Hct% RBC count MCV fl MCH pg MCHCg/dl Retics % NRBCs/100 WBCs

Full termnewborn 18.4 ± 2.2 61 ± 7.4 5.1 ± 1.0 108 ± 9 35 ± 4 36 ± 2 3.2 ± 1.4 7.0

7 days 17.9 ± 2.5 56 ± 9 5.1 ± 1.0 99 ± 11 32.5 ± 4 35 ± 2 0.5 3-10

2 weeks 15.6 ± 2.6 46 ± 7.3 - - - - 1.0 3-10

3 months 11.3 ± 0.5 33 ± 3.0 4.5 ± 0.7 88 ± 8 29 ± 5 33 ± 3 0.7 0

1 year 11.8 ± 0.5 39 ± 2.0 45 ± 0.7 78 ± 8 27 ± 4 32 ± 3 0.9 0

3-6 years 12.7 ± 1.0 37 ± 3.0 4.5 ± 0.7 78 ± 8 27 ± 3 33 ± 2 1.0 0

10-13 years 13.2 ± 1.0 39 ± 3.0 4.7 ± 0.6 86 ± 8 27 ± 3 33 ± 2 1.0 0

Male adult 16.0 ± 2.0 47 ± 5.0 5.2 ± 08 85 ± 8 29.5 ± 2.5 33 ± 2 1.0 0

Female adult 14.0 ± 2.0 42 ± 5.0 4.8 ± 0.6 85 ± 8 29.5 ± 2.5 33 ± 2 1.0 0

Table 6. Pediatric reference ranges for commonly used white cell parameters

Age Total WBC Neutrophils Lymphocytes Monocytes EosinphilsCount 10o/L % % % %

Birth 9 - 30 61 31 6 2

12 Hours 13 - 38 68 24 5 2

24 Hours 9.4 - 34 61 31 6 2

1 week 5.0 - 21 45 41 9 4

2 weeks 5.0 - 20 40 48 9 3

1 Month 5.0 - 19 35 56 7 3

6 Months 6.0 - 17 32 61 5 3

1 Years 6.0 - 17 31 61 5 3

2 Years 6.0 - 17 33 59 5 3

4 Years 5.5 - 15 42 50 5 3

6 Years 5.0 - 14 51 42 5 3

8 Years 4.5 - 13 53 39 4 2

10 Years 4.5 - 13 54 38 4 2

16 Years 4.5 - 13 57 35 5 3


36

less than 1.5 lakhs/mm3. This is seen in infections,immune destruction and acute leukemias.Thrombocytosis in children is usually reactiveas in infections but may also occur in conditionssuch as hemorrhage, collagen vascular diseases,tumors and drugs. A few clues as to the presenceor absence of functional or qualitative plateletdisorders can be got by a careful perusal of awell stained, finger prick, peripheral blood smear.Small platelets are seen in Wiskott Aldrichsyndrome and giant platelets are seen in reactiveconditions and functional platelet disorders.

Complete blood counts innewborns

The CBC is an invaluable tool for evaluatingconditions like infections, anemia and jaundicein newborns. It must be kept in mind thatpremature infants have a lower Hb than terminfants and RBCs are usually macrocytic innewborns. The common causes of anemia innewborns are blood loss (due to placentaltransfusion, feto-maternal hemorrhage, umbilicalcord hemorrhage, twin-twin hemorrhage andinternal hemorrhage, iatrogenic), hemolysis and

aplasia. Acute blood loss produces anormochromic, macrocytic anemia while chronicblood loss produces a hypochromic, microcyticanemia7. The CBC is also useful in thehaemotological scoring for sepsis in newbornsTable 3 and for this the parameters used are:WBC count, Differential count, Platelet countNucleated red blood cells (NRBC) count, (gotfrom the peripheral blood smear study) andNeutrophil morphology (vacuolation of thecytoplasm, toxic granules etc.),

Peripheral blood smear

Careful evaluation of a well prepared bloodsmear is a very important part of evaluation ofhematologic disease especially in the pediatric agegroup. Many diseases are diagnosed by lookingat the peripheral blood smear (Fig.5 - 8). It alsoserves as a check to discern the otherwiseunexplainable changes and artifactual changes inthe CBC. Table 4 (eg. detection of sources oferrors in estimating CBCs). Hence it is vital forthe clinician to interpret the CBC in the light ofthe findings in the peripheral blood smear.

Fig. 5 Hereditary elliptocytosis (PS) Fig. 6 Sickle cell anemia (PS)

2003;5(1):37

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NEWS AND NOTES

2nd Multidisciplinary CME in Pediatrics 2003

The Department of Pediatrics of All India Institute of Medical Science, New Delhi is organizingthe 2nd Multidisciplinary CME in Pediatrics 2003 on March 29-30, 2003 at AIIMS.The theme of this year’s CME is “Pediatric Emergency and Intensive Care”. The CME willconsist of symposia, case discussions and lectures by distinguished faculty of the Institute.Registration is limited and will be done on ‘first come first served basis”.The registration fee is Rs 750/- for general delegates and Rs 500/- for postgraduate students.The fee should be sent as demand draft drawn in favor of ‘CME Program in Pediatrics” payableat New Delhi before 15 February 2003.For further details or correspondence contact:Dr. Pankaj Hari or Dr. Rakesh Lodha, Department of Pediatrics, AIIMS, New Delhi 110 029,Phone No. 6561123 (Ext 4858, 3621)E-mail: [email protected], rakesh_lodha @ hotmail.com. Fax: 011-6862663.

Summary - Clinicians and the CBC1. The CBC is an invaluable diagnostic tool.2. The clinical should optimize the use of this

diagnostic modality.3. The CBC should be interpreted cautiously in

light of the methodology used to do the testand the clinical condition.

4. Interaction between the clinician and thelaboratory is very important.

5. No laboratory test can fully replace the roleplayed by a carefully taken history andmeticulous physical examination, indiagnosing pediatric ailments.

Fig. 7 Malarial parasite (PS) Fig. 8 Malarial parasite (PS)


38

RECENT ADVANCES IN CHILD-HOOD ACUTE LYMPHOBLASTICLEUKEMIA

* Kusumakumary P

Over the past few decades there has beendramatic improvement in the prognosis ofchildren with leukemia. Incremental advances intreatment success span a 30 year period, duringwhich ALL has gone from a uniformly fataldisease to one with an overall cure rate greaterthan 75%.1,2,3 (Fig - 1&2.) The strategic successresults from a series of advances like therecognition of diversity of ALL, indentificationof clinical and biological prognostic factors thatresulted in tailoring therapy according toprognostic factors and avoidance of potential lateeffects of therapy. Improved techniques ofsupportive care and intensive therapy forrecurrent disease have also contributed totreatment success.

ALL is characterised by an excessiveaccumulation of lymphoblasts within the marrowspace and to a variable extent elsewhere. Thegenesis of childhood ALL in still not known.According to current view the leukemic processis assumed to begin in a single hematopoietic cellof any lineage varying in maturity from themultipotential primitive stem cell to the moredifferentiated cells. The critical defect is intrinsicto the cell and inheritable by its progeny.Establishment of an accurate diagnosis based on

available morphologic, biologic and cytogeneticdata is essential for risk categorization.

Morphologic, immunologic and molecularcharacterization of lymphoblasts has confirmedthat ALL is a biologically heterogeneousdisorder. This heterogenecity reflects the fact thatleukemia may develop at any point during themultiple stages of normal lymphoiddifferentiation. Morphologic classification usesthe criteria such as cell size, nuclear cytoplasmicratio, nuclear shape, number and prominence ofnucleoli etc. and groups ALL into L1, L2 & L3(FAB system). Cytochemical stains have beenstudied but the practical use of this type ofinformation is limited and has been supplantedby more sophisticated immunologic techniquessuch as immunopheno-typing and cytogenetics.

Immunophenotype

Lymphoblasts expresses on the cell surfacea variety of antigens which correspond todevelopmental stages of ‘T’ & ‘B’ cells. In theearly 70’s, 3 immunologic subtypes weredelineated ‘T’ cells, ‘B’ cells and non T/ non Bcells or null cells. Using receptors for sheeperythrocytes, approximately 20% of paediatricpatients with ALL were found to have ‘T’lymphoblasts, cell surface immunoglobulin in 1-2% and the remaining patients were consideredto have null cell leukaemia. The development ofheterogeneous antisera and monoclonalantibodies against human leukemia associatedantigens indicated that approximately 80% ofpatients formerly presumed to have had null cellALL had common ALL antigen CALLA (CD-10) on their cell surface. This leukemic subset isnow referred to as CALLA +ve ALL. Using a

* Addl. Professor & Head,Division of Pediatric OncologySAT Hospital, TrivandramKerala.

HEMATO-ONCOLOGY

2003;5(1):39

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panel of monoclonal antibodies associated withvarious stages of B cell differentiation along withinformation on the presence or absence ofcytoplasmic and surface immunoglobulininvestigators have classified B-lineage ALL intodiscrete stages according to the degree ofdifferentiation or maturation. Although more than200 different monoclonal antibodies arecommercially available that can detect antigens

associated with different haemotopoietic lineages,only a few of those antigens are truly lineagespecific4.

The specific markers are CD-79a for B-lineage, cytoplasmic CD-3 for ‘T’ lineage andcytoplasmic a -MPO for myeloid cells. Thesensitive markers include CD-19 for B - lineage.CD-7 for T - lineage, and CD-13 and CD-33 for

Fig.1. Improvement in survival of children with acute lymphoblastic leukaemia (A. Bleyer,H. Sather)

Fig.2. Outcome of 2600 children with acute lymphoblastic leukaemia stratified according toprognostic groups and treated by the Childrens Cancer Study Group (W.A. Bleyer, H. Sather)


40

myeloid cells. With this panel a firm diagnosis ofALL is possible in all cases.

Immunophenotyping has the potential toimprove risk assessment. Mature B cell ALL hasa poorer prognosis than earlier ‘B’ lineagesubgroup. Patients with B cell precursor ALLwhose lymphoblast manifest CALLA (CD 10)have a more favourable prognosis. Identificationof immunoglobulin gene rearrangement is helpfulin confirming the B cell precursor lineage of ALLcells otherwise devoid of other B cell markers. Tcell has distinctive immunologic as well as clinicalfeatures. 3 stages of normal intrathymicdifferntiation have been proposed, early,intermediate and late, but prognostically thesetypes are not important as in the case of B celllineage.

Not all cases adhere to a specific lineage.Expression of myeloid associated antigens onotherwise typical lymphoblasts has beenrecognised since the early 1980’s and is knownas mixed lineage leukaemia. The biologic basisfor the appearance of mixed lineage leukaemiais not understood.

Cytogenetics and moleculargenetics

Lymphoblasts from various patients withALL differ with respect to DNA content, cytoge-netic abnormalities, kinetic properties and cellderivation. All these differences bear on theultimate clinical manifestation of the disease.Clonal chromosomal abnormalities are found inmore than 90% of childhood ALL cases5. Theseabnormalities can be either numerical orstructural. In children ploidy is the most importantprognostic factor, with hyperdiploidy having abetter prognosis. Those is pseudo diploidcategory with normal chromosome number butother chromosomal abnormalities liketranslocations have a relatively poor prognosis.The worst prognosis occurs in the rare group of

patients with near haploidy which has an eventfree survival less than 25%. Translocations aremost frequent in the pseudodiploid group andthere appears to be an association between certaintranslocations and immunophenotypes. Thet.(8;14), t.(4;11) and t. (1:19) are associated withhigh rates of early treatment failure but the mostcommon ALL translocation t.(12;21) appears tohave a good prognosis. The t.(9;22) (philadelphiachromosome) was one of the first leukaemictranslocation described and remains thetranslocation with the worst prognosis inpaediatric ALL. One exception is a subset ofchildren with philadelphia chromosome positiveALL and low preseenting leukocyte count or goodinitial response to prednisolone therapy whoappear curable with intensive chemotherapyalone.

Molecular analysis has proved indispensablefor identifying certain prognostic andtherapeutically important genetic subtypes ofALL. E.g. Childhood ALL associated with cryptictranslocation, t.(12;21) (p13.q22) results in afusion gene TEL - AMLI which confers afavourable response to treatment. The t (1;19)(q23; p13) translocation results in fusion of thetranscriptional activation domain of E2A onchromosome arm 19 p with the DNA bindinghomeodomain of PBX located on chromosome 1and the ALL cases that express E2A-PBX proteinappear to have a poor prognosis. Approximatelythree quarters of childhood ALL cases haveidentifiable specific genetic abnormalites withprognostic relevance6.

Pharmacogenetics

The field of pharmacogenetics studies thegenetic basis for the difference betweenindividual responses to specific drugs. It isreasonable to assume that individual patients willdemonstrate differences in drug metabolism andresponse which may have important effects ontherapeutic efficacy and toxicity. One of the best

2003;5(1):41

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examples of pharmacogenomic effects in ALLrelates to the isoforms of thiopurine methyltransferase (TPMT). This is a crucial enzyme thatmetabolizes parent 6 - mercaptopurine into aninactive metabolite. Patients homozygous forTPMT null mutation have been shown to havesevere 6MP related toxicity, whereasheterozygous patients appear to have moderatetoxicity with 6MP7. Again, patients with TTgenotype were reported to have an increased riskof methotrexate induced oral mucositis.

Risk classification

It is common practice to assign patients onthe basis of prognostic factors into different riskgroups and to tailor therapy accordingly.Unfortunately there is no consensus on specificrisk criteria and the terminology that best definesthe relapse hazard in discrete group of patients.Initial leucocyte count and age at diagnosis havetraditionally provided the most reliable basis forpatient stratification. Age between 1 & 9 yearsand a leukocyte count <50 x 109/L are commonlyused as minimal criteria for low risk B-Cellprecursor ALL. In the vast majority of clinicaltrials, T-cell ALL is considered to carry astandard risk of relapse and is treated accordingly.Among other clinical and biologic variables thatmight be used to guide the selection of treatment,early treatment response as indicated by the rateand degree of clearance of leukaemic cells fromblood or bonemarrow during the early phase ofremission induction therapy is perhaps the mostimportant8. This factor shows independentprognostic significance in both B-cell precursorand T-cell ALL, with slow early responseconferring a poor prognosis.

Minimal residual disease (MRD)

The availability of immunologic andmolecular techniques has increased our abilityto detect residual disease at levels below thesensitivity of morphologic evaluation. These

techniques include cytogenetics, flow cytometricsorting and immunophenotyping, clonogenicassays and detection of leukaemia specific DNAor RNA sequences by southern blot orpolymerase chain reaction. The most widelyapplicable system available for the measurementof MRD involves polymerase chain reaction ofgene rearrangements. The risk of relapse asdefined by MRD analysis was more accurate thanthat achieved by clinical methods, but single timepoint analysis fails to account for he efficacy ofsubsequent treatment. It is becoming clearer thatthe rapid lowering of MRD levels below 10-4

correlates well with relapse free survival9.Conversely patients with whom MRD doesn’tclear below this point or more slowly goes belowthe same level have a higher risk of relapse.Multiple issues remain to be clarified and eventualapplicability in clinic are still under investigation.

Advances in treatment

The treatment should be specific andintensive enough to induce a complete remissionand attempt a cure by keeping the child inremission long term. Since ALL is aheterogeneous disease, it is inappropriate to givesingle treatment regimen for all children withALL.

Infants with ALL are often considered tobe a unique subgroup and treated with intensivechemotherapy. ALL-L3 is again a separate entityand should be treated with short term intensivechemotherapy as for B Cell lymphomas. Mostinvestigators would divide the remaining casesof ALL into low risk, standard risk and high riskgroups. Unfortunately there is no uniform criteriafor defining ALL risk groups.

Irrespective of the risk group for which it isintended, all treatment regimens embody 4 majorphases; remission induction, CNS preventivetherapy, consolidation and maintenance therapy.In patients with high risk ALL, intensive


42

remission induction seems to have improvedtreatment outcome. Less intensive remissioninducion may be sufficient for low risk casesprovided they are given post inductionintensification therapy.2,3 In the clinical trial bythe Childrens Study Group it was observed thatintensive induction - consolidation therapy did notadd benefit to ‘intermediate risk’ patients whoreceived delayed intensification therapy. Mostremission induction regimens include minimum of3 drugs and maximum of 5 drugs. Recentlydexamethasone has replaced prednisolone as aglucocorticoid of choice to improve outcome, butdexamethasone may be associated with higheracute and long term complication rates. Failureof induction therapy occurs in less than 5% ofchildren with ALL.

With the recognition that cranial radiationpredisposes to neuropsychiatric andneuroendocrinologic disturbances in youngchildren, alternative CNS prophylaxis approacheswere evaluated. Several randomised studiesdemonstrated that cranial radiation could beeliminated in children with low and intermediaterisk ALL if intrathecal methotrexate in continuedat intervals throughtout maintenance.Investigators of the Berlin-Frankfurt-Minsterconsortium has demonstrated that a radiation doesas low as 12Gy, together with intrathecalmethotrexate and effective systemicchemotherapy can provide adequate CNS controleven in patients at high risk of CNS relapse10.

Early studies demonstrated that withoutadditional therapy, most patients relapse within ina median period of 1-2 months. To effectivelyprevent relapse, post induction therapy mustsuppress leukaemic growth and providecontinuing leukaemic cytoreduction withoutpermitting the emergence of a drug resistantclone. The first strong proponents of the benefitsof this phase of therapy were the West GermanBFM group. Now most investigators agree that

intensification therapy is necessary to maximiseearly cell kill. Delayed intensification, doubledelayed intensification and so called protocol IIIwere demonstrated to improe outcome further11.Treatment strategies differ, optimum timing, doseintensity are yet to be clarified.

Methotrexate administered weekly and 6 -Mercaptopurine given daily constitutes thestandard back bone of continuation treatment.Tailoring doses to the limits of tolerance has beenassociated with improved outcome. The additionof intermittent pulses of vincrisitine andprednisolne to the antimetabolite regimen improvessurvival. The optimal length of maintenancechemotherapy has not been established. It is likelythat intensification of therapy has a bearing onthe optimal duration of therapy12. Most centerstreat patients for a total of approximately 2.5 to 3years. Attempts to shorten the treatment durationto 12 months or 18 months have resulted ininferior overall event free survival in tworandomized trials. Philadelphia chromosomepositive leukaemia is the only subtype of childhoodALL that clearly benefits from allogenicbonemarrow transplantation from an HLAmatched donor.Treatment of relapse

Bone marrow relapse is the principal formof treatment failure in patients with ALL. Marrowablative chemotherapy followed by allogenictransplantation of stem cells is the ultimate formof treatment intensification and is thereforepreferred treatment for patients with early bonemarrow relapse who have attained a secondremission. Patients with late bone marrow relapseshould be treated with intensive chemotherapyalone because they have a reasonable chance ofcure with intensive chemotherapy.Complications of therapy

Delayed sequelae observed in survivors ofALL include second neoplasm,neuropsychological changes, endocrine

2003;5(1):43

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study group from 1981-1995. Leukaemia 2000;14: 2205 - 2222.

3. Margolin J, F, Stenber C P, Poplack D G. Acutelymphoblastic leukaemia. In: Pizzo PA; PoplackDG eds., Principles and practice of PediatricOncology Ed-4. Lipincott Williams and Wilkins,2002; pp 489-529.

4. Borowitz MJ. Immunological markers inchildhood acute lymphoblastic leukaemia.Hematol Oncol clin N. Am 1990; 47: 743-765.

5. Chessells JM, Swansbury GJ, Reeves B, BalieyuCC, Richards SM. Cytogenetics and prognosisin childhod lymphoblastic leukemia : results ofthe MRC UKALL X. Br J Hematol 1997; 99:93- 100.

6. Martinz - Climent JA,: Molecular cytogeneticsof childhood hematological malignancies.Leukaemia 1997; 11: 1999-2021.

7. McLeod HL, Krynetski EY, Relling My et al.Genetic polymorphism of thiopurinemethyltransferase and its clinical relevance forchildhood acute lymphoblastic leukaemia.Leukaemia 2000; 14: 567 - 572.

8. Gayon PS, Desai AA, Bostrom BC, et al. Earlyresons to therapy and outcome in childhoodacute lymphoblastic leukaemia. Cancer 1997; 71:959 - 965.

9. Dworzak MN, Froschl G, Printz D etal;Prognostic significance and modalities of flowcytometeric minimal residual disease detectionin childhood acute lymphoblastic leukaemia.Blood 2002; 99: 1952 - 1958.

10. Counter V, Schrappe M, Arico M, et al. Role ofcranial radiotherapy for childhood T-cell acutelymphoblastic leukemia with high WBC countand good response to predisolne. J Clin Oncol1997, 15 ; 2786 - 2791.

11. Lange BJ, Bostrum B, Cherlow JM, et al. Doubledelayed intensification improves event - freesurvival for children with intermediate risk acutelymphoblastic leukaemia: A report from theChildren’s Cancer group. Blood 2002; 99: 825 -833.

12. Childhood ALL Collaorative group. Durationand intensity of maintenance chemotherapy inacute lymphoblastic leukaemia: Over view of 42trials involving 12,000 randomized children.Lancet 1996; 347: 1793-1788.

dysfunction and cardiomyopathy. Long termneurologic and neuropsychological functioningmay be impaired following CNS therapy evenwhen irradiation is avoided.

Future challenges

The major issue in the therapy of ALL ishow to improve the outcome of high risk children.Current investigations have focused in the use ofnewer therapeutic agents and interventions basedon the persistence of MRD. The role of multidrugresistance in ALL remains to be determined.Newer chemotherapeutic agents undergoing trialsin ALL include carboplatin and the combinationof ifosfamide and etiposide. The use ofmonoclonal antibodies to deliver toxins directlyto the leukaemic cell is undergoing activeexploration.

A recent report demonstrated that childhoodALL has an angiogenic phase suggesting atherapeutic role for anti angiogenic drugs suchas endostatin. Perhaps the most exciting approachto prevention of relapse lies in the use of noveltumour vaccines that are designed to preventrelapse by stimulating the host immune responseto leukaemic cells.

The current research in developing genetherapies like suicide gene insertion, antisensemodulation, antigen upregulation or biologicmodifiers of disease progression, includingimmunotoxins or differentiating agents will addto out potential for making leukaemia anotherchildhood illness that can be conquered.

References

1. Rubinitz JE, Pui CH. Recent advances in thebiology and treatment of childhood acutelymphoblastic leukaemia. Curr Opin Hematol1997, 4: 233-241.

2. Schrappe M, Reiter A, Zimmermann M, et al:Long term results of four consecutive trials inchildhood ALL performed by the ALL-BFM


44

HYPOVOLEMICHYPERNATREMICDEHYDRATION IN INFANTS

* Nair PMC

Dehydration is classified as isotonic,hypotonic or hypertonic, based on the serumosmolality. Hypernatremic dehydration isusually caused by gastroenteritis, but can resultfrom other causes also (Table 1). This type ofdehydration is very dangerous. Thehyperosmolar state can lead to brain shrinkage,venous thrombosis and subdural capillaryhemorrhage. In addition, rehydration can causecerebral oedema and subsequent seizures. At thesame time early recognition is extremely difficultand dehydration is often missed. Henceawareness is very important for the generalpediatrician so that early treatment is possible toavoid the fatal complications.

Hypovolemic hypernatremia is thecommonest in pediatric practice, the mostcommon cause being acute gastroenteritis, wherethe water loss is far greater than salt loss. 90%of cases occur in children below 2 years and theworst outcome is in babies less than 6 months1,2,3.We had a few cases of rotavirus gastroenteritiswith associated hypernatremia. Similar reports arethere in literature 4,5.

Iatrogenic cases due to formula feeds andtreatment of diarrhoea with wrong dilution of oralrehydration solution has also occurred in our

experience with infants. The formula-fed infantis at higher risk of hypernatremic dehydrationduring common situations which reduce bodywater (reduced intake, increased evaporativewater loss due to fever or elevated environmentaltemperature and diarrhoea)3. Infants withhypernatremic dehydration secondary to so calledlactation failure are typically encountered duringthe first and third weeks of life6. There infantsare strikingly lethargic, dehydrated andmalnourished with a weight loss equal to or morethan 10% of the body weight. The first signs ofneonatal dehydration include failure to have bowelmovements or the presence of urate crystal,combined with weight loss7. Daily weightevaluation, careful breastfeeding assessment andearly routine postpartum follow-up are effectivemethods to prevent hypernatremic dehydrationand promote breastfeeding.

Why hypovolemic hypernatremicdehydration most common ininfants?

Infants are worst affected with hypovolemicdehydration, because of (a) immaturity of thekidney to excrete an excess sodium load, (b)limited ability to express thirst and (c) reliance onothers to provide appropriate fluids7.

Early recognition is extremely difficult anddehydration is often underestimated, as watershifts from the intracellular to the extra-cellularcompartment. There may be fever, tachycardiawith poor perfusion and hypotension withhypovolemia. The skin appears thick, doughy andmay even be warm. The mucous membrane isdry, with depressed fontanel and sunken eyes.An important findings is intense thirst, Once

* Consultant, Neonatal & PICU,Child Healh Department,Sultan Qaboobs University Hospital,Muscut, Sultanate of Oman

CRITICAL CARE

2003;5(1):45

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hypernatremia, brain cells shrink leading to ruptureof briding vessels with hemorrhages(subarachnoid and parenchymal), thrombosis andocclusion of dural sinuses8,10,11. During rapidrehydration with relatively hypotonic IV fluids,excess water enters the cerebral cells, leading torebound cerebral oedema and seizures.

Permanent cognitive impairment, cerebraldysfunction, spastic hemi and monoplegias andseizure disorders have been reported. Childrenwith early neurologic symptoms have a 50%chance for neurologic sequelae10. Extensivelateral, central pontine and extra-pontinemyelinolysis have been reported12,13. Renal veinthrombosis and renal tubular injury may alsooccur14. hyperglycemia and hypocalcemia canoccur15. Mortality in acute case with serumNa> 160mmol/L is around 45% (10-70%), whileit is around 10% in chronic hypernatremia16.Calculation for volume and waterdeficit is done in the followingsteps

I. Consider percentage of dehydration (10%)

Table 2. Diagnostic approach

1. Careful History2. Assessment of clinical volume status3. Neurologic examination4. Determination of serum electrolyte andblood urea nitrogen5. Determination of plasma glucose6. Determination of serum osmolality7. Simultaneous determination of urinary elec-trolyte8. Blood gas estimation for base deficit.

serum Na is > 145 mmol/L or osmolality is > 300mOsm/kg, the thirst center in hypothalamus isstimulated and water will then be ingested.Another mechnaism tightly controlling serumosmolality is the release of Anti-DiureticHormone form the neurohypophysis making thekidney to concentrate urine, thus conserving freewater 3,8.

Complications

The most hazardous effect of hypernatremiais on the brain. During the development of

Table 1. Hypernatremic dehydration

I. Hypovolemic hypernatremia (loss of water in excess of salt)1. Extra - renal loss : GI loss: vomiting, diarrhoea2. Cutaneoues loss : Excessive sweating: extensive burns, increased insensible water

loss in ELBW babies.3. Third space loss : Ileus, Peritonitis4. Renal loss : Osmotic diuresis secondary to glucose, Mannitol, urea

II. Euvolemic hypernatremia (Pure water loss)1. Insensible loss : Fever, high ambient temperature, hyperventilation2. Renal loss : Central and nephrogenic diabetes insipidus3. Insufficient fluid intake : Decreased level of consciousness

Lack of access to waterIII. Hypervolemic hypernatremia

(Pure sodium excess - Usually iatrogenic)1. Salt poisoning : Hypertonic IV solutions; incorrect preparation of infant

formula / ORS2. Mineralocorticoid excess : Cushing syndrome3. Salt water drowning


46

II. Then calculate free water deficit in 3 steps

a) Usual (normal) total body water (TBW) =weight g x 0.6 (L)

b) Current TBW= normal TBW

(Even osmolality can be considered in the placeof Na)

c) Free water deficit = Normal TBW - Currentbody water.

III. A simple calculation for free water deficit is

4 ml x weight x (sodium difference (deficit) if Nabelow 170 mEq/L)

If serum Na > 170 mEq/L it is 3 ml x weight xNa difference 21,22.

IV. Free water has to be calculated, withoutelectrolytes.

V. The rest of volume is calculated witheletrolytes

VI. Combined deficit and maintenance fluidworks out roughtly, 1/4 to 1/3 isotonic, when runin over 24-48 hours.

Considering the above points, therapy guidelinesare as follows:

Therapy Guidelines

1. Immediate rehydration

The first priority in a dehydrated patient isrestoration of intravascular volume. Give 20 ml/kg normal saline (0.9% sodium chloride) orRinger lactate sodium over 30-45 minutes If theresponse is poor, repeat a bolus of 10 ml/kg over30-45 minutes.

2. Correction of sodium and water deficit

Once the patient is stable, correct serum

sodium slowly over 48-72 hours with 5%Dextrose and 0.45% sodium chloride solution.Therate of reduction of serum Na should be less than0.5 mmol/hour and should not exceed 10 mEq/L/24 hours. If extracellular osmolality is dereasedrapidly, an osmotic gradient may develop betweenthe brain and plasma resulting in a net movementof water into the brain producing cerebral odema,seizures and even permanent neurologic sequelaeand death. Avoid hypotonic solution. Initial fluidsshould have sodium concentration of 75 mEq/L.

3. Maintenance fluids and electrolyte mustbe given in addition to calculated water deficit inquantities sufficient to replace urinary output andinsensible losses.

Maintenance fluids

< 10 kg = 100 ml/kg/24 hrs.

for each kg above 10 kg

11-20 kg = 50 ml/kg/24 hrs + 1000 ml

21 kg and above = 20 ml/kg/24 hrs foreach kg above 20 kg + 1500 ml

4. Oral rehydration solution

When Na level has decreased to150 mmol/L, oral fluids can be substituted. (Oralrehydration solution 10 ml/kg with each diarrhoealstool). Appropriate and slow reduction is serumNa level has been attained with classic WHOORS as well as with rich starch based, low sodium(60 mmol/L) ORS with less incidence ofcomplications 17,18,19.

5. Treatment of complications

If seizures occur, treat carefully withanticonvulsants, IV 3-5 ml/kg of 3% sodiumchloride, mannitol or hyperventilation and closemonitoring of serum Na.

measured Na coneNormal Na cone

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6. Dialysis

In acute severe hypernatremia with serumNa > 300 mmol/L peritoneal dialysis with 4.5intially and later 1.5% dialysis fluid isrecommended.

Hemodialysis and hemofiltration have beensuccessfully tried20, but venoarterial access maybe difficult.

Hyperglycemia more often is anaccompaniment more so when the serum Na isvery high. Primary correction is not attempted.But occasionally it is done but with great caution.Hypocaclemia may also occur which is to betreated cautionsly.

Conclusion

Hypovolemic hypernatremic dehydration inan infant is an acute medical emergency andshould be diagnosed and treated promply, asmortality is around 45% and can be as high as70%. Diagnosis is extremely difficult anddehydration is most often underestimated.Complications result not only from hypernatremiabut from aggressive and inappropriate rehydration.The serum sodium should be lowered slowly andcautiously using the fluid that will not drop theserum sodium level by more than 10 mmol/24 hrs.

References

1. Mansir T, Sarlangue J, Fayon M, Babin JP,Demarquez JL. Severe Hypernatremia due tofeeding error. Arch Pediatr 2000; 7: 430.

2. Adrogue HJ, Madias NE. Hypernatremia. N EngJ Med 2000; 342; 1493-1499.

3. Mishkin MB, Simonet M, Lawrence C, van WhySK. Hypernatremia in infancy. Curr Opin Pediatr1998; 10: 156-160.

4. Jacobson J, Bohn D. Severe hypernatremicdehydration and hyperkalemia in an infant withgastroenteritis secondary to rotavirus. AnnEmerg Med 1993; 22: 1630-1932.

5. Ho L, Bradford BJ. Hypernatremic dehydrationand rotavirus enteritis. Clin Pediatr (Phila) 1995;34: 440 - 441.

6. Scott ER, Amy K. Neonatal hypernatremicdehydration secondary to lactation failure. J AmBoard Fam Pract 2001; 14: 155-158.

7. Rosa M, Carmela M, Teresa M, Lucia M, Ma-rina G. Incidence of dehydration andhypernatremia in exclusively breastfed infants.J Pediatr 2001; 139: 673-675.

8. Hilliard TN, Marsh MJ, Malcolm P, MurdochIA, Wood BP. Sagittal sinus thrombosis inhypernatremic dehydration. Arch PediatrAdoles Med 1998; 152: 1147.

9. Schulman M. Organic osmolytes in the brain ofan infant with hypernatremia. N Eng J Med 1994;331: 1776 - 1777.

10. Fiordalisi I. Central nervous system complica-tions during hypernatremia and its repair. ArchPediatr Adoles Med 1994; 148: 539-540.

11. Mocharla R, Schexnayder SM. Glasier CM. Fatalcerebral oedema and intracranial hemor-rhage associated with hypernatremic dehydra-tion. Pediatr Radiol 1997; 27: 785-787.

12. Brown WD, Caruso JM. Extrapontine myeli-nolysis with involvement of the hippocampusin three children with severe hypernatremia. JChild Neurol 1999; 14: 428-433.

13. Al Orainy IA, O’ Gorman AM, Decall MK. Ce-rebral bleeding, infarcts and presumedextrapontine myelinolysis in hyprnatremic de-hydration. Neuroradiology 1999; 41: 144-146.

14. Palevsky PM. Hypernatremia. Semim Nephrol1998; 18: 20-30.

15. Hogan GR. Hypernatremia problems inmanagement. Pediatr Clin North Am. 1976; 23:569 - 574.

16. Conley SB. Hypernatremia. Pediatr Clin NorthAm 1990; 37: 365-372.

17. Farthing MJ. Hypernatremia, acute diarrhoeaand oral rehydration therapy. Lancet 1992; 339-936

18. Lyngkaran N, Yadav M. Rich starch low sodiumoral rehydration solution (ORS) in infantilediarrhoea. Med J Malaysia 1995; 50: 141-144.


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NEWS AND NOTES

INDIAN ACADEMY OF PEDIATRICSIX EAST ZONE PEDICON

&XIV BIHAR STATE PEDICON

GAYA, BIHAR

Date: 28th Feb. - 2nd March 2003

Venue: Hotel Royal Residency, Bodh - Gaya

Registration Fees (Includes CME)

Before Before Before Before Spot30 July 02 20 Sept. 02 30 Nov. 02 30 Jan. 03

IAP Members Rs. 700/- Rs. 800/- Rs.1000/- Rs.1100/- Rs.1200/-

Accompanying Person Rs. 600/- Rs. 700/- Rs. 900/- Rs.1000/- Rs.1100/-

Post Grad. Students Rs. 400/- Rs.500/- Rs.600/- Rs.700/- Rs.800/-

Payment should be made only through “DEMAND DRAFT”In favour of “IX EAST ZONE PEDICON” Payable at GayaNO CHEQUE WILL BE ACCEPTED.

No extra charge would be taken for “Banquet”CALL FOR ABSTRACTS WILL BE DETAILED SOON

Secretariat address for correspondence:Dr. Vijay K. Jain(Orgainsing Secretary)A.N. Road, Gaya, Bihar - 823 001.Phone: 0631 - 220966 0631 - 422374 0631 - 433537E-mail: [email protected]

19. Singh M. Hypernatremia and ORS. IndianPediatr 1995; 32: 377-378.

20. Mc Graw ME, Chambers TL. Correction ofhypernatremia with continuous arterivenoushaemodiafiltration. Arch Dis Child 1990; 65: 528-630.

21. Mary K Choukair MD. Fluids and Electrolytes.In: The Harriet Lance Hand Book 15th Edn.,© by Mosby Inc., 2000; pp 232-237.

22. John E Stork. Dehydration and Electrolyte Dis-orders. In: Manual of Emergency pediatrics, 4thEdn., Eds., Robert M Ruce MD, WB Saunders,Philadelphia, 1992; pp 171

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APPROACH TO THE CHILD WITHFEVER AND RASH

* Benjamin B

Introduction

The child with febrile illness and rash is acommon problem presenting to the pediatrician.The medical literature is replete with elegantdescriptions of the classical infectious exanthems.

The field of childhood febrile rashsyndromes is an evolving one with several newdevelopments over the years. Improved livingstandards and widespread immunization havecontributed to eradication or reduced prevalenceof some febrile exanthems1. On the other hand,fresh challenges are posed by the spectrum ofnew and emerging infections2. There is alsoconcern about the reemergence of old diseasesin new locations or in more virulent forms3. Newsyndromes have been recognized and knownclinical entities have had their etiologicalassociation with viral agents defined4. The roleof toxins and immune mechanisms in thepathogenesis of disease has been the subject ofstudy5,6. In this evolving context, this article seeksto provide an overview of this topic that focuseson a clinical and differential diagnostic approachto the problem.

It would be pertinent to mention certainaspects of febrile rash syndromes that might havea bearing on their evaluation. A specific clinicalsyndrome may have several predisposing causes.

* Consultant Pediatrician,Malar Hospitals, Chennai - 20.

Conversely, a specific agent may be associatedwith more than one syndrome. Gianotti-Crostisyndrome (GCS) has, for example beenassociated with several agents including hepatitisB, Epstein-Barr (EBV) and Coxsackie virus.Stevens-Johnson syndrome (SJS), toxicepidermal necrolysis (TEN) and erythemanodosum are examples of hypersensitivitydisorders that may be triggered by factors asdiverse as infections, drugs, connective tissuedisease and malignancy. Human herpesvirus 6(HHV-6) may cause classical roseola or, rarely,an infectious mononucleosis (IM)-likesyndrome (4). Variations in host-parasiteinteractions may lead to varied spectrum ofpresentation of a specific illness, ranging fromsubclinical to disseminated and fatal disease.

Classification

Fever and rash are featured in a large anddiverse number of conditions. Table 1 providesa classification of categories of such diseases,with representative examples in each category.Infectious diseases remain a predominant causeof febrile illness with rash in children throughtoutthe world, particularly in developing countries.There are geographic variations in the prevalenceof specific illnesses and the physician shouldfamiliarize himself with exanthems that arecommon in his area of practice.

Pathogenesis of rash

There is now a better understanding of themachinisms involved in the production of rash andother manifestations of many childhoodexanthematous illnesses, though many questionsremain unanswered. The superantigen theory

PRACTITIONER’S COLUMN


50

postulates that a bacterial exotoxin stimulatesimmune activation and release of cytokinemediators, which results in rash or vasculitis thatcharacterizes the disease5-7. Examples includeerythrogenic toxins A - C in scarlet fever, toxicshock syndrome (TSS) toxin-1 in staphylococcalTSS, exfoliative toxins A and B in staphylococcalscalded skin syndrome (SSS) and an unidentifiedtoxin in Kawasaki disease (KD). In dengue fever,the hemorrhagic/shock variant occurs inindivuduals who have developed non-neutralizingantibodies from a primary infection when asecondary infection with another serotype leadsto immune enhancement of viral replication8.Hemorrhagic rashes are mediated bythrombocytopenia, vasculitis or coagulopahty.

Clinical presentation

Knowledge of the natural history and thecourse of specific childhood illnesses with feverand rash should form the basis of a properevaluation of the problem. Detailed hisotry anddiligent physical examination will enablerecognition and differentiation of most childhoodfebrile rash syndromes. Table 2 lists relevantaspects of history and examination that meritspecial attention.

History

Certain exanthems have typical agedistribution patterns. Roseola occurs in infancy.KD predominantly in children under five years.

Table 1. Classification of illness associated with fever and rashInfections

Viral BacterialVaricella Scarlet feverMeasles Scalded skin syndromeRubella Toxic shock syndromeRoseola (HHV-6, HHV-7) Meningococcemia*Erythema infectiosum (Parvovirus B19) Gream negative sepsis*HFM disease (Coxsackie A16 virus) Infective endocarditis*Enteroviral exanthems Spirochetal infections*HSV infections LeptospirosisInfectious mononucleosis (EBV) SyphilisViral hemorrhagic fevers (e.g. Dengue)* Lyme diseaseHepatitis B

Rickettsial, Fungal, Heminthic and Protozoal infectionsInflammatory disease

Systemic-onset juvenile rheumatoid arthritis (Still’s disease)Systemic lupus erythematosusVasculitis syndromes: e.g. Kawasaki disease, Henoch-Schonlein purpura *Inflammatory bowel disease

Malignancy: e.g. Leukemia, lymphomaMiscellaneous

Histiocytosis syndromesErythema multiforme major (Stevens-Johnson syndrome)Toxic epidermal necrolysis* Conditions Commonly associated with purpuric rash.

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and infectious mononucleosis in older children andadolescents. The age distribution of scarlet feverreflects that of streptococcal throat infections.Transplacental immunity protects the young infantagainst a variety of viral exanthems. Asusceptible neonate may however experiencedisseminated forms of varicella and herpessimplex virus (HSV) infections. As several ofthese infections are highly contagious, history ofcontact with a case in the household, school orday-care setting would be relevant. Animmunization history may be sought for thevaccine-preventable diseases such as measles,rubella and varicella. A recent drug history wouldbe relevant as antibiotics, often prescribed forchildren with fever, might be responsible for anallergic rash.

Prodrome

A detailed elucidation of the duration,severity, symptoms and sequence of events in theprodromal (pre-rash) stage of the illness mayprovide early clues to the diagnosis. Certain

illnesses such as rubella and varicella areassociated with short and mild prodromal phase.In some bacterial infections such asmeningococcemia and scarlet fever, the briefprodrome is associated with severe constitutionalsymptoms. The prodromal stages of measles androseola have a similar duration of 3-4 days, butstrikingly different symptomatology. The formeris associated with florid symptoms of respiratoryand conjunctival catarrh in contrast to the paucityof findings to explain the fever in the latter. Thechronic inflammatory diseases tend to follow acourse of prolonged pyrexia with rash appearingat a variable stage in the illness.

Rash

The stage of rash is often the defining partof the illness. A detailed evaluation of the natureof the rash including its onset, distribution,evolution and resolution is often of diagnostic help.The presence of associated mucosal lessions(enanthem) and involvement of other organs andsystems will also need to be assessed.

Table 2. Relevant history and physical examination in a child with feverand rash

HistoryAge and sexContact historyImmunization historyPast history of specific exanthemsRecent medications (e.g. Antibiotics, anticonvulsants, sulphonamides etc)Recent travelUnderlying illness (e.g. Immunodeficiency, heart disease, bowel disease etc.)

ProdromeFever, associated symptoms, sequence of events

RashOnset, nature, distribution, evolution and resolution

General examinationVital signs, cardiorespiratory status, sensorium

Systemic examinationEvidence of organ involvement


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Erythematous maculopapular rashes areseen in many childhood exanthems such asmeasles, roseola and rubella. ‘Scarlatiniform’denotes a punctate papular eruption in anerythematous background that is typically seenin scarlet fever, but also occurs at the onset ofstaphylococcal and streptococcal toxin-relatedSSS and TSS. Lesions with clear centers andactive erythematous margins are featured inrheumatic fever and Lyme disease. Acutemeningococcemia is heralded by purpuric rash,which may progress rapidly to confluent skinnecrosis (purpura fulminans). Allergicvasculities such as Henoch-Schonlein purpura(HSP) are associated with palpable purpura.Examples of vesicular eruption include varicella-zoster and HSV infections, hand-foot-mouth(HFM) disease and Steven Johnson Syndromewhereas large bullae are seen in SSS and ToxicEpidermal Necrolysis. An infiltrative type of rashis seen in histiocytosis and the malignancies.

Distribution of rash

A generalized rash distribution is seen inmeasles, scarlet fever and disseminated HSVinfections, whereas a central, predominantlytruncal, rash is noted in varicella, roseola andStill’s disease. A peripheral distribution withacrodermatitis and relative sparing of the trunk isa feature of GCS and HFM disease and late KD.Prominence of rash in the flexures is a feature ofscarlet fever (Pastia’s lines) and SSS and anextensor distribution over the limbs is seen in HSP,erythema nodosum and the later stages orerythema infectiosum. A localized skin lesion isa feature of Lyme disease (erythema migrans),herpes xoster (dermatomal distribution), anthrax,streptococcal erysipelas and pseudomonalecthyma gangrenosum.

Evolution and resolution of rash

Several chilldhood exanthems follow acharacteristic pattern of evolution that aid in their

recognition. The rash of measles, for example,commences over the hairline of the forehead andneck and progressess caudally over the face,trunk, upper and lower limbs over a 3-day period.Fine desquamation and residual brown stainingcharacterize the convalescent stage. In varicella,there is rapid evolution of each lesion throughstages of macule, papule, vesicle, pustule,umbilication and scab over a 24 - 48 hour period.The lesions appear in crops over a 3 - 4 day periodresulting in a characteristic pleomorphicappearance. The 3-stage rash of erythemainfectiosum evolves from erythema of the cheeksto a generalized maculopapular rash, which thengradually fades centrally to leave a reticulatedlacy pattern over the limbs. In dengue, the eruptionmirrors the biphasic course of the illness; atransient generalized macular erythema at theonset is followed by a maculopapular rash in thesecondary phase. It becomes purpuric in the fewpatients who develop a hemorrhagic diathesis. InKD, a truncal maculopapular or polymorphousrash is followed in the second week by painfuledema and erythema of the distal extremities,which progresses to the characteristic periungualdesquamation. The eruption of SSS evolves frompainful scarlatiniform erythema to flaccid blisterformation. Resolution is by generalizeddesquamation with crusting and fissuring aroundthe mouth and eyes. A desquamative resolutionis also seen is scarlet fever, TSS and TEN.

A polymorphic eruption and thecharacteristic ‘target lesions’ are seen in SJS,whereas in GCS, there are monomorphic firm,flat-topped dusky papules that later turn purpuric.

A typical facies is seen is some febrile rashsyndromes. A malar rash is noted in systemiclupus erythematosus (SLE) (butterflydistribution) and early erythema infectiosum(slapped-check appearance). A flushedappearance of cheeks with circumoral pallor is afeature of scarlet fever. Periorbital and perioral

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crusting gives the face a characteristic appearancein children with SSS.

In many childhood exanthems such asmeasles, erythema infectiosum, varicella, roseola,scarlet fever, SSS, TEN and HSP, the presenceof rash is invariable and essential for thediagnosis. In certain conditions, cutaneousmanifestations are present in a variable proportionof cases and their diagnosis is based also on othercriteria. For example rash is reported to occur ina majority (80-96%) of children with SLE9 andStill’s disease (95%) but is only an occasionalfeature of other illnesses such as leptospirosis(10%). The overall incidence of rash in InfectionsMononucleosis is 3-13%; this rises to 90% inpatients administered ampicillin or amoxycillin andthe reason for this phenomenon remainsunexplained.

Enanthem

Involvement of mucocutaneous junctions isa salient feature of some childhood febrileexanthems and their appearance may besufficiently distinctive to be of diagnostic help. Inmeasles, conjunctivitis is accompanied bystomatitis and the pathognomonic Koplik spots.Congested pharynx and ‘strawberry’ tongue arecommon to scarlet fever and KD. In the lattercondition, these are accompanied by non-exudative conjunctivities and cheilitis. PrimaryHSV infections involve the eyes or mouth (HSV-1) or genitalia (HSV-2). These sites may also beinvolved in SJS, TEN and TSS. Oral ulcersaccompany the acral lesions in HFM disease. Itis, therefore, evident that the clinical evaluationof a child with fever and rash in incompletewithout a thorough examination of mucosal sitesfor ‘hidden’ lesions.

There may be associated involvement ofother specific organs and systems whoserecognition may provide additional diagnosticclues. Exudative tonsillitis is a feature of scarlet

fever and IM. Cervical or generalizedlymphadenopathy may accompany a variety ofinfections such as rubella, IM and syphilis as wellas in inflammatory disorders such as KD andStill’s disease. Hepatomegaly with or withoutsplenomegaly may be present in IM,leptospirosis, still’s disease and GCS. Chronicsymmetrical polyarthritis is a cardinal feature ofStill’s disease. Arthropathy is also featured inmany inflammatory and connective tissuedisorders and some infections such as rubella andparvovirus B19 infections in older girls. Severemyalgia is present in leptospirosis, TSS anddengue. Myopericarditis is noted in rheumaticfever and some enteroviral syndromes.Polyserositis may complicate Still’s disease, SLEand dengue shock syndrome. Nephropathy is afeature of SLE, HSP and leptospirosis,Encephalopathy with convulsions may complicateseveral viral and rickettsial infections.Multisystem involvement is a feature ofdisseminated varicella and HSV infections,leptospirosis, TSS and the chronic inflammatorydisorders. A progressive course leading to shockand multiorgan failure is noted in meningococcaland gram-negative sepsis, TSS and the viralhemorrhagic and shock syndromes.

Drug reactions

Adverse reaction to drugs is oftenoverlooked as a cause of fever and rash inchildren. The mechanism is often related toallergy by any of the known mechanisms ofhypersensitivity. In some instances, as inampicillin-induced rash, the pathogenesis isunknown. The rash is usually urticarial ormaculopapular, but may be vesicular,hemorrhagic, desquamative, nodular orpolymorphous. It may present as a recognizableclinical syndrome as in SJS, TEN, serumsickness, photodermatitis, exfoliative dermatitisor fixed drug eruption. Predisposing factorsinclude past or family history of drug allergy and


54

underlying immunodeficiency. Drug-relatedfactors predisposing to rash include dose,frequency, duration and route of administration.Topical application is most likely to sensitize, oraladministration least so. Commonly implicateddrugs include antibiotics, sulphonamides andanticonvulsants. The incidence of antibiotic-associated fever and rash is estimated to be 0.2-1.6%10. Diagnosis rests on careful history, clinicalsuspicion and exclusion of other causes.Discontinuation of the offending medicationwould usually result in quick resolution.

Diagnosis

Many childhood exanthems such as measles,varicella, roseola, erythema infectionsum andHFM disease follow a fairly typical pattern andthis permits a purely clinical diagnosis of theseentities. Dianostic criteria combining clinical andlaboratory features have been accepted fordiseases such as rheumatic fever, SLE and KD,which have varied features and no specificdiagnostic test11,12.

Hematological variations are common andmay serve as useful adjuncts to diagnosis, thoughthey are neighter constant nor specific. Significantelevation of erythrocyte sedimentation rate is seenin the inflammatory disorders and malignanciesand is used to minotor disease activity andprogress. Various cytopenias are noted in viralinfections and SLE. Neutrophilia occurs in Still’sdisease, KD, rheumatic fever and most bacterialinfections (unless overwhelming). Markedthrombocytosis is characteristic of KD. Aperipheral smear would provide diagnostic cluesin infectious mononucleosis and leukemia. Thecoagulation profile would be deranged in childrenwith fever and a hemorrhagic rash.

Serologic tests for high or rising antibodytitres are used for detection of viral, spirochetalor rickettsial infections and autoantibody testsmay aid the diagnosis of connective tissue

diseases. Smear from the cutaneous lesion mayprove useful in meningococcemia (gram stain),rickettsial infection (immunofluorescence),varicella (Tzank smear) and HSV infections.Bacterial cultures can be taken from appropriatesites such as the blood, skin lesions, CSF andpharynx in bacterial infection syndromes. Newertechniques such as polymerase chain reaction arebeing using for a widening variety of infectionsthought their availability and cost may be limitingfactors. More extensive investigation includingimaging, bone marrow aspiration and diagnosticbiopsies would be considered for a few childrenwith unexplained fever and rash to excludeinfection, inflammatory disease or malignancy.

Diagnostic dilemmas

These arise on account of atypicalpresentations of the classic exanthems oroverlapping features between variousexanthematous illnesses. Measles, for instance,may be attenuated in children with partialimmunity acquired passively transplacentally oractively through past infection or immunization.At the other end of the clinical spectrum, a severehemorrhagic form of measles with high mortalityis recognized in malnourished, immuno-compromised children. SJS may present withoutrash and with stomatitis as its sole manifestationin up to 25% cases, making it difficult todifferentiate from other conditions such as herpeticgingivostomatitis. Parvovirus B19 may beconfused with SLE as both have, in common,manifestations such as fever, malar rash,arthropathy, anemia and induction ofautoantibodies13. Confluent skin erythema andtenderness progressing to bullae are common toSSS and TEN. KD may minic other exanthemssuch as scarlet fever and leptospirosis becauseof overlapping eatures. In immunodeficientpatients, diagnostic difficulties occur because ofatypical presentation and protracted courses ofinfection.

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Management

The management is largely symptomatic andsupportive in the self-limited viral exanthems.Antipyretic measures may be used, particularlyin those prone to febrile convulsions. Maintenanceof skin hygiene, and antipruritic measures wouldhelp prevent secondary infection frombreakdown of cutaneous barrier in children withvesiculobullous eruptions such as varicella, SSS,SJS and TEN. Attention to hydration andnutrition is important in children with poor intakeon account of stomatitis in measles, SJS and HSVinfection and with excessive skin fluid losses inthose with extensive bullous eruptions.

A more aggressive management approachincluding ventilatory and circulatory support iswarranted in patients with a progressive courseand potentially life threatening complications suchas bleeding, shock, respiratory failure,encephalopathy or multiorgan dysfunctionsyndrome. The various hemorrhagic and toxicshock syndromes come under this category.

Specific management

Antimicrobial drugs are used in themanagement of specific infections. Examplesinclude penicillin for meningococcemia, scarletfever and spirochetal infections, cloxacillin foreradicating the primary infective focus in TSSand SSS and appropriate antibiotics in infectiveendocarditis, sepsis in immunocompromised hostsand secondary bacterial sepsis in conditions suchas varicella, SJS, TEN and SSS. Acyclovirreduces mortality and morbidity in disseminatedHSV and varicella in immunocompromised hosts.When varicella is anticipated to be more severeas in adolescents, adults and secondary cases inthe family, early use of acyclovir within 24 hoursof onset of rash has been shown to abort itsprogress14. Antimicrobial drugs against fungal,protozoal and viral infections are available for a

variety of infective complications inimmnodeficient children with fever and rash.

other examples of specific managementmodalities include the use of intravenousimmunoglobulin in KD12, blood components incoagulopathic states and the use of steroids,immunosuppressive and non-steroidal anti-inflammatory drugs in the chronic inflammatoryand connective tissue diseases11.

From a management perspective, it wouldbe useful to differentiate the following groups ofchildren presenting with fever and rash:

1. Known vital or virus - associated syndromewhich can be identified because of its distinctiveclinical morphological pattern and which isexpected to follow self-limited natural course.Clinical diagnosis and supportive treatmentwould suffice in this group. Examples in thiscategory include classical measles, rubella,varicella, GCS and HFM disease.

2. Non-specific fever and rash where a specificdiagnosis is awaited and depends on clinicalevolution of illness and rash or on laboratoryfetures. Two subgroups may be differentiated.

a. A presumed viral exanthem where thechild looks well and a benign course is anticipated.Examples include roseola and enteroviral illness.

b. An ill looking child with presumedbacterial infection or potential for seriousconsequences, (e.g. Scarlet fever, early SSS, KD)where immediate investigation and/or specifictreatment could be initiated6.

3. A critically ill child with progressive courseand compromised vital signs (with features ofsepsis, shock, respiratory failure or alteredsensorium) where urgent referral, admission,monitoring, investigation and prompt institution


56

of optium specific and supportive treatmentcould minimize risk of death or sequclae.Examples in this group includemeningococcemia, late TSS and SSS, and the viralhemorrhagic fevers6,15.

4. Prologned fever and rash group where aplanned protocol of investigation can beundertaken to establish the nature of the illnessbefore commencing appropriate treatment.

Conclusion

Unraveling the problem of the childpresenting with fever and rash represents achallenge of diagnostic skills even to the astuteclinician. The numerous infectious, inflammatoryand drug-related problems and their variedpresentations that need identification anddifferentiation highlight the complexity of theproblem. However, with a sound knowledge ofthe locally prevalent common childhoodexanthems and a methodical clinical evaluationof the nature and course of the illness through itsprodromal and exanthematous stages, supportedin a few patients with further investigation, thisdiagnostic exercise can be an interesting andrewarding experience. There remain severalmysteries with regard to this important field ofchildhood disease that will maintain the interestof clinicians and researches in the years ahead.

References

1. Reported vaccine-preventable disease - UnitedStates, 1993, and the Childhood ImmunizationInitiative. MMWR Morbid Mortal Wkly Rep1994; 271: 651 - 652.s

2. Holland DJ. Emerging viruses. Curr Opin Pediatr1998; 10:34 - 40.

3. Gubler D, Clark G. Dengue/dengue hemorrhagicfever: the emergence of a global health problem.Emerg Infect Dis 1995; 1:55-57.

4. Asano Y, Yoshikawa T. Human herpesvirus-6and parvovirus B19 infections in children. CurrOpin Pediatr 1993; 5:14-20.

5. Herman A, Kappler JW, Marrack P, Pullen AM.Superantigens: Mechanism of T-cell stimulationand role in immune responses. Annu RevImmunol 1991; 9:745-772.

6. Resnick SD. Staphylococcal toxin-mediatedsyndromes in childhood. Semin Dermatol 1992;11:11-18.

7. Leung DYM, Meissner HC, Fulton DR, MurrayDL, Kotzin BL, Schlievert PM. Toxic shock syn-drome toxin-secreting Staphylococcus aureusin Kawasaki syndrome. Lancet 1993; 342:1385-1388.

8. Halstead SB. Pathogenesis of dengue:challenges to molecular biology. Science 1988;239; 476 - 481.

9. Takei S, Maeno N, Shigemori M, Clinical featuresof Japanese children and adolescents withsystemic lupus erythematosus: results of 1980-1994 survey. Acta Pediatr Jpn 1997; 39: 250-256.

10. Iwata S, Akita H. Adverse effects of antibiotics.Acta Paediatr Jpn 1997; 39: 143-154.

11. Lehman TJ. A practical guide to systemic lupuserythematosus. Pediatr Clin North Am 1995; 42:1223 - 1238.

12. Dejani AS, Taubert KA, Gerber MA, et al. ST,M, Bie W, sDiagnosis and therapy of Kawasakidisease in children. Circulation 1993; 87: 1776-1780.

13. Nesher G, Osborn TG, Moore TL. Parvovirusinfection mimicking systemic lupuserythematosus. Semin Arthritis Rheum 1995; 24:297 - 303.

14. Balfour HH Jr. Clinical aspects of chicken poxand herpes zoster. J Int Med Res 1994; 22 Suppl1:3A-13A.

15. Dengue hemorrhagic fever: diagnosis,treatment, prevention and control. Geneva,Would Health Organization, 1995.

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MANAGEMENT OF ACUTEASTHMA

* Vijayasekaran D

The prevalence of asthma is increasingthroughout the world both in developing anddeveloped countries1. For the past one decade,the concepts regarding the pathophysiology andconsequently the management principles ofasthma has changed. Asthma is no longer abronchospastic disease. In addition to thebronchospasm the underlying mucosalinflammation play a major role in outcome ofasthma. In susceptible individuals, thisinflammation increases bronchial hyperresponsiveness resulting in recurrent episodes ofwheezing, breathlessness, chest tightness andcough particularly at night and in the earlymorning. Several triggers unique to each patientinitiate the inflammatory process. During an acuteexacerbation, treatment of acutebronchoconstriction remains an important aspectof management. However controlling theunderlying inflammation is an important aspectto prevent recurrence of such attacks. Onceasthma is diagnosed, the following managementprinciples to be followed strictly lest recurrentacute exacerbation of asthma is inevitable whensuch children are exposed to inciting events. Theimportant management principles are (a) the childshould be one long term maintenance therapy withinhaled corticosteroids to control theinflammation (b) to be away from inciting /precipitating triggers (c) understanding the nature

of disease and change in the life style. (d)practicing the correct inhaler technique withappropriate inhalation devices(e) to monitor thecourse of the disease with peak expiratory flowmeter for objective assessment.

Natural course of asthma

Asthma is a chronic disease like rheumatoidarthritis characterized by repeated courses ofremission and exacerbation. The disease isusually mild and episodic in nature during the initialcourse and when it gets established becomespersistent. The presistent asthma can beclassified as mild/moderate and severe persistenttypes. All the four divisions of chronic asthma(mild intermittent, mild persistent, moderatepersistent and severe persistent) on exposure toinciting events (triggers) may present as acuteattack with varying severity. (Fig.1)

Acute asthma

Most acute attacks of asthma are usuallymild responding to conventional line ofmanagement and at times it is so severe that thechild needs intensive therapy and rarely evenventilatory support. The frequency of acute attackis disproportionately higher for children living inurban and low-income environments and urbanchildren often use the emergency department asthe primary source of asthma care2.

Assessment of acute asthma

Since acute asthma always endangers life,attention should be focussed on maintenance ofairway, breathing and circulation. Beforecommencing treatment, careful brief history andclinical examination should be done emphasizing

* Asst. Professor of PediatricsInstitute of Child Health & Hospital forChildren, Egmore, Chennai 600 008.

IJPP - IAP CME 2001


58

Fig 1. Natural course of asthma

the following aspects for successful outcome.The brief history should include factors regardingthe duration of symptoms, exposure to triggers,medicine taken, food intake, prior emergency visitsand hospitalization. Quick physiologicalexamination should be done to assess the level ofconsciousness, check the vital signs, activity, workof accessory muscles and extent of wheeze(Table 1).

Though several methods are available toassess the severity of acute attack of asthma,

Table 1. Acute asthma - Assessment

the pulmonary score based on the age, respiratoryrate, wheezing and activity of accessory muscleis found to be the simple and practically feasibleone on emergency visits (Table 2).

Based on the above, the severity of an acuteasthma can be classified as mild, (PS<3),moderate (PS 4-6) and severe (Ps>6). Childrenabove 6 years can be encouraged to do peakexpiratory flow rate along with PS score forobjective assessment as PS correlates will withPEFR (PEFR > 70 = PS<3; PEFR 40-70 = PS 4-6; PEFR < 40 = PS > 6)3.

History : onset / duration / hospitalisationWalking : normal; prefer sitting; bend forwardSpeech : sentences; phrases; wordsAccessory muscles : +; ++; paradoxical. thoraco abdominal movementWheeze : expiratory; exp & insp.; silent chestPulse : Infant>160; preschool; >120; school; > 110R.R : <2mo>60; 1-12mo>50;1-5yr. >40SaO2 : 95-100; 91-95%; <90%Pulsus paradoxus : <10; 10-15; >15;

Mild Moderate Severe

Acute Asthma

Maintenance Therapy - NoTriggers - Yes

Hereditary Asthma Environment

Intermittent Mild Presistent Moderate Presistent Severe Presistent

→ → Chronic Asthma → →

↑↑

↑

↑

↓

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Treatment of acute attack ofasthma

When a child present with acute asthma,assessment and treatment should gosimultaneously. Decisions should be based uponclinical evaluation coupled with experience andmethodical approach is essential to avoid missingof the associated problems.

Mild acute asthma

Inhaled bronchodilators are the main stay oftherapy to relieve acute spasm, can beadministered through nebuliser along withsupplement oxygen. The ideal does of salbutamol(2.5 mg) 0.5 ml (below 20 kg) as nebulisersolution diluted with 2ml of normal saline to benebulised for 5 minutes. If there is no adequateresponse, the above dose can be repeated oncein 15 minutes with a maximum of three doses. Ifnebuliser is not available salbutamol can bedelivered by metered-dose inhaler with spacer.A number of studies indicate that MDI iscombination with a spacer is as effective and mostcost efficient than nebuliser.4 Four puffs (100 mcg/ puff) are given every 15 minutes for a maximumof three times. After each puff the child shouldtake atleast five breaths to ensure adequateintrapulmonary delivery. Significant proportionof children with mild attack can be safelydicharged from the outpatient service with theabove therapy. Salmeterol, longer acting beta

agonist, is not indicated in the treatment of acuteasthma due to the relatively slower onset ofaction5

While discharge, detailed information aboutthe use of medicines should be given as writtenprotocol and advised to go for follow-up withprimary care provider or to attend specialityclinic (Asthma Clinic) for comprehensive follow-up. (Fig. 2)

Moderate acute asthma

Children who have not responded to abovesaid protocol can be classified as having moderateacute attack which needs immediateadministration of systemic steroids in addition tothe liberal use of humidified oxygen (3-6 litres)either through canula or mask. Thoughintravenous methyl prednisolone (2mg/kg/statfollowed by 1mg/ kg sixth hourly) is thepreferred one, other steroids like hydrocortisone(10mg/kg to start with followed by 5 mg/kg 6hourly) or oral prednisolone (2mg/kg/day) canbe used depending upon the availability. Delayedinstitution of steroids will reflect delayedresolution of symptoms though onset of actionof steroid take 6 to 8 hours. Since ipratropiumhas synergistic bronchodilator effect withsalbutamol, ipratropium (125mcg = 0.5ml below1 year and 250mcg = 1ml above 1 yr) can beadded along with salbutamol especially in themanagement of acute attack of asthma in

Table 2. Pulmonary score (PS)

Respiratory RateScore Wheezing Accessory Muscle use

< 6 Yr > 6 Yrs (Sternocleidomastoid)

0 < 30 < 20 None No apparent activity1 31 - 45 21 - 35 Terminal expiration Questionable increase2 46 - 60 36 - 50 Entire expiration Increase apparent3 > 60 > 50 Inspiration and expiration Maximal activity


60

extremes of ages. Ipratropium blocksacetylcholine receptors at the neuromuscularjunction of bronchial smooth muscle resulting inbronhodilation. Though ipratropium produceless bronchodilation than beta agonists, theduration of action may be prolonged.6

Ipratropium should always be used along withbeta agonists because of its mild bronchodilatoraction7.

The bronchodilator nebulisation should becontinued for every one to 2 hours depending uponthe response. If the response is good the childcan be discharged with continuation of inhaledbronchodilators (Salbutamol) 100 mcg 2-3 puffs5-6 times per day along with oral steroids withproper discharge advice as mentioned.

Severe Acute Asthma

If the above protocol fails, the attack shouldbe classified as acute severe attack and the

following drugs can be tried in addition to thedrugs which have already been instituted..Though the added bronchodilator effect oftheophylline is controversial when maximumdose of inhaled beta agonists has been used,few pulmonogists prefer to use aminophyllineat this juncture (5mg/kg in 20 ml of normal salineto be run for 20 minutes 8th hourly iv) asaminophylline achieves the desired effect byacting on several sites (stimulation of respiratorycentre, stimulation of mucociliary mechanism,direct spasmolytic action on bronchial smoothmuscle, stimulation of muscles of respiration,immuno modulation of T cell, in addition to thewell recognised actions like phosphodiesteraseinhibition and adenosine inhibitor mechanism).Since the therapeutic window of aminophyllinein narrow the dose should be cautiously planned.Children below 10 years tolerate better. The doseshould be modified on concurrent administrationwith other drugs like macrolides cemetidinewhich interfere with aminophylline metabolism.

Assessment

Mild Moderate Severe

• Beta 2 agonists Q15 mts • O (3-6 lit/mt) • O2 - (SaO2 > 95)• Nebuliser / MDI spacer • Beta1 agonists Q 15 min • Nebu beta2 agnonists Q15 mts.• Ipratropium • Ipratropium • Ipratropium• O2 useful • Steroids oral • Aminophylline / Mgso4• Steroids oral? • Terbutaline IV

• Steroids IV

Good Response Ventilatory Support

Home

↓

↓

↓ ↓↓

Fig 2. Management of acute asthma

↓

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Few studies supported that a dose ofmagnesium sulphate (25 to 50mg/kg in 20ml ofnormal saline to be run as infusion of 30minutes)may be worth the trial in severe asthma.Magnesium works by modulating calciumchannels causing a decrease in acetycholine withsubsequent bronchodilation and inhibition ofhistamine release from mast cells.8 If the responseto magnesium sulphate is good, one more dosecan be administered after 6 hours otherwise thedrug should be abandoned, Adverse effectsinclude flushing, nausea and hypotension.

When the obstruction of the airway is severe,the tidal volume is too low to allow any aerosolmedication into intrapulmonary tree. Childrenwho show poor response to aerosol drugs shouldbe benefitted with systemic intravenous beta2agonists before other invasive measures..Intravenous terbutaline is preferred, to be startedwith 10mcg/kg/stat as an infusion for 10 minutesfollowed by 2 mcg/kg/ every hour. Salbutamolcan also be used at a dose of 0.5 to 5 mcg / kg /min. Majority of children with acute asthma dorespond to above protocols if associatedcomplications are looked in to and mechanicalventilation may rarely be resorted.

Monitoring

Monitoring of vital signs like respiratoryrate, pulse rate, sensorium and intake - outputis important at every level of asthma care. Pulseoximetry and peak expiratory flow rate play asignificant role in the objective assessment andSaO2 should be maintained above 95% withliberal use of oxygen. Arterial blood gas analysisshould be considered for children with continuedO2 saturation of less than 90% on maximaloxygen therapy. Measures should be taken tomaintain adequate nutrition and fluids. Theadverse effects of beta2 agonists like tremor, V /Q mismatch, agitation and hypokalemia shouldbe anticipated.

Differential diagnosis of acutewheeze

All that wheezes is not asthma and so whena child presents with first attack of acute wheezenot responding to the above line of therapy themost common differential diagnosis should beconsidered is the nonopaque foreign bodyaspiration especially in toddlers. Other diseasesto be considered in the differential diagnosisare heart failure, metabolic acidosis andstructural anomalies of airway.

Discharge advice

80% to 90% of mild attacks of acute asthmamay respond to the above protocol and the childcan be discharged. However if a child fails toimprove with therapy, he or she is moved up tothe next category (mild to moderate & moderateto severe). Before discharge the child’spulmonary score should be less than 2 or PEFR80% or above the depending upon the responsethe child should be advised to continue bothinhaled bronchodilator and steroids.

Ventilatory Support

The use of accessory muscles of respiration,a pulsus paradox greater than 12 mm Hg,diaphoresis, inability to recline, hypercapnea, ora peak expiratory flow rate less than 40% ofpredicted all suggest that the patient has norespiratory reserve. If the patient does notimprove within 4 hours of initiating therapy in theemergency department, or the patient requiresventilatory support.

Complications associated withacute asthma

1. Neublised medications should be deliveredwith oxygen rather than air, asbronchodilators can occasionally causetransient oxygen desaturation because ofventilation perfusion imbalance (V/Q


62

imbalance). Administering humidifiedoxygen 3-5 litres in the nebuliser circuit willavoid the above complication and O2administration is preferable even in childrenwith mild acute attack.9

2. Associated pulmonary complications likeunderlying pneumonia, airleak syndromeshould be thought of if the respiratorydistress continues, where skiagram chestplay a major role.

3. Since the asthmatic children miss regularfood intake, underlying metabolicderangement is inevitable and respiratoryacidosis gets added up with thebronchospasm is severe. Though respiratoryacidemia may be useful to stimulate therespiratory centre initially, when thecarbondioxide accumulation is fast (5mm ofHg Co2 per hour) the child needs ventilatorysupport.

4. Asthmatic children should be allowed one toone and half times and requirement ofmaintenance fluid to avoid water retention(reduced ADH secretion).

Health education

Children who develop acute severe attackmay be prone to get repeated attacks if they arenot placed on maintainance steroid. Avoidanceto trigger play a significant role in children withasthma. Illiteracy, poor medical compliance, poorfamily infrastructure are the risk factors for acuteattack. Again, the cycle of poor regular careleading to emergency department visits andsubsequent inadequate or undertreatment ofchronic asthma contribute to the increasingmorbidity and mortality of children with asthma.10

So health education plays a major role to breakthis vicious cycle and it has been stronglyrecommended that child with asthma should haveregular visits with primary care providers

especially after discharge from emergency room,The whole family members especially the parentsshould be imparted asthma education during eachvisit to achieve positive asthma care and long termremission.References

1. Burr ML, BK Butland, King S and E.Vanghan -Williams. Changes in asthma prevalence: twosurveys 15 years apart. Arch Dis Child 1989;(64): 1452 - 1456.

2. Wasilewski Y, Clark N, evans D, et al. Factorsassociated with emergency department visitsby children with asthma: implications for healtheducation. Am J Public Health 1996;86: 1410-1415.

3. Smith S, Hodge, Baty J. The pulmonary score:An asthma severity measure for children in theemergency department. Acad Emerg Med 1998;5: 383.

4. Colacone A, Afilano M, Wolaove N, et al. Acomparison of albuterol administered bymetered dose inhaler (and holding chamber) orwet nebulizer in acute asthma (comments).Chest 1993; 104: 835 - 841.

5. Corbridge TC, Hall JB. The assessment andmanagement of adults with status asthmaticus,Am J Respir Crit Care Med 1995;151: 1296-1316.

6. Higgins RM, Stradling JR, Lane DJ. Shouldipratropium bromide be added to beta agonistsin tratment of acute severe asthma? Chest 1998;94:718-722.

7. Zore J, Ogborn J, Pulsic M. Ipratropium bromide:what role does it have in asthma therapy?Contemp Pediatr 1998;4:81-94.

8. Rolla G, Bucca C, Caria E. Dose related effect ofinhaled magnesium sulfate on histamine bron-chial challenge in asthmatics. Drug Exp Clin Res1988; 14609-612.

9. Seidenberg J, Mir Y, Vander Hardt H.Hypoxaemia after nebulised salbutamol inwheezy infants. The importance of aerosol ac-tivity. Arch Dis Child 1991; (66): 672-675.

10. Smith SR, Strunk RL. Acute asthma in the pedi-atric emergency department. Pedatr clin N Am1999; 46(6): 1145-1165.

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SOME COMMONDERMATOLOGICAL PROBLEMSIN CHILDREN

* Jayakar Thomas

Introduction

It is estimated that about 25% to 30% of alloutpatient visits to a pediatrician consist ofdermatological problems and around the samepercentage of all outpatients to dermatologistcomprises the pediatric age group. Thispresentation discusses the diagnosis andtreatment of some of the commonly seenchildhood dermatoses.

Scabies

An infection causes by the itch mite,Sarcoptes scabiei var hominis, scabies is by thecommonest of all skin disorders in our country.The cutaneous manifestations are the much-overrated burrows in the interdigital spaces oron the flexure of the wrists, and numerous itchysmall excoriated urticarial papules at these sitesand over the elbow, axillae, inner thighs, buttocks,and periumbilical area. Diagnosis can be madeby the history of intense itching and the associatedclinical findings. The management of scabies isnot as easy as it is so often mentioned. The goodold sulphur ointment (3%), still rules roost inspiteof its offensive odour and messey state afterapplication. A good scrub bath followed byrubbing the ointment from neck to toes for threedays and three nights, followed by a hot bath is

the advice given. Benzyl benzoate (25%)emulsion is also used in the same manner. Thencomes gamma benzene hexachloride (1%), whichis claimed to be useful in a single 12-hourapplication. Decades have passed and now wehave the newer molecule, permethrin. Used as a5% cream, it is found to be scabicidal in a shortperiod of two to four hours.

Impetigo

Impetigo is a common disease of children.Its highly contagious nature is responsible for theformer name impetigo contagiosa. A break in theskin such as occurring with a cut, an insect biteor skin trauma is enough to allow the causativeagents, streptococcus or staphylococcus to growunder the stratum corneum of the skin. Thedisease tends to involve the face more often.Clinically the lesion starts as vesicles or pustulesand rapidly forms honey-coloured crusts. Spreadfrequently occurs from autoinoculation.Treatment is directed primarily towards sparklingpersonal hygiene. Saline compresses areacceptable to debride the crusts. Systemicantibiotics such as penicillin and a wide range oftopical antibiotics serves good purpose asremedies. The choice of topical antibiotics for longhad been framycetin sulphate. The last decadehas found sisomycin sulphate very useful. Therecent trend has been towards using topicalmupirocin (1%) ointment that is claimed to bemost effective and not warranting the use ofsystemic antibiotics.

Tinea capitis

Children seem to be infected bydermatophytes more often on the scalp than on

* Consultant Dermatologist,Kanchi Kamakoti CHILD Trust Hospital,& Apollo Hospital, Chennai

IJPP - IAP CME 2001


64

other sites. Clinically, tinea capitis starts as acircumscribed patch of scales, gray to black incolour. Quite often the lesions tend to getsecondarily infected with bacteria, to form aboggy swelling that shows signs of acuteinflammation. This is the usual kerion type oftinea capitis. History of recurrent tonsuring maycontribute in diagnosing most cases. Form thetreatment point of view, it may be said that oralgriseofulvin 250mg to 500mg daily for aboutthree to six months is quite satisfactory, in termsof resolution of skin lesions and prevention ofrelapses. But, of late, the physician is beingconfronted by cases of griseofulvin resistance.The imidazoles like ketoconazole andintraconazole have now come to offset thissituation of griseofulvin resistance. Intraconazole/ketoconazole (100mg) daily for two weeks hasshown to give excellent results in most cases ofdermatophyte scalp infection.

Pityriasis Versicolor

Pityriasis versicolor (more often called tineversicolor) is a non-inflammatory yeast infectioncaused by Pityrosporon orbiculare. It affectshealth children, with nearly half of them in thetropics. Principle sites of involvement are theupper back, upper chest, sides of the neck andthe proximal arms. Asymptomatichypopigmented well defined macules and patchesthat reveal slight scaling when scratched (coupde ongle sign) are the typical lesions.Occasionally the lesions are hyperpigmented anditchy. Managment of pityriasis versicolor canbe a very tiring and trying exercise. Prudencedemands routine laundering of clothing. Thebenzoic-salicylic acid combination has been thetreatment of choice even since Whitfielddescribed it in 1907. Gone are those days andnow we have more than a dozen topicalantifungals useful in the treatment of pityriasisversicolor. These include 2% miconazole, 1%

clotrimazole, 1% ketoconazole, and 1%tolnaftate. But the newer ones are those belongingto the group of allylamines (e.g. terbinafine). Onepercent terbinafine today is the recent topicalanswer to the treatment of pityriasis versicolor.

Urticaria

Hives or urticaria is known to affect largenumber of children. It is said that all childrensuffer from at least one episode of urticaria.Urticaria is a reaction patterns of the skincharacterized by transient, itchy, oedematous, anderythematous swelling (wheals) of the skin,caused by a wide range of agents acting frominside the body, outside the body, or both. Whenthe condition goes on for more than six to eightweeks, it is classified as chronic urticaria, and asacute urticaria when seen for less than six weeks.Intermittent attacks of ‘acute on chronic urticaria’have also been noticed. The purpose of thiscategoriation as acute and chronic is from thetherapy point of view. Acute urticaria respondswell to sufficient doses of antihistamines, whilethe chronic type requires a thorough workup forits aetiology. It is mandatory that bacterialinfection and gastrointestinal parasiticinfestations are ruled out or are treated. However,antihistamines from the gold standard in thetreatment of urticarias. When have today aconglomeration of antihistamines ranging fromsedate and potent to the non-sedate and lesspotent ones. It has become a useful changingtrend to turn towards the non-sedate antihista-mines for the treatment of chronic urticaria. Thenewer antihistamines like astemizole, terfanidine,cetirizine, loratidine and desloratidine have all beenfound useful. A once daily dose of 5mg to 10mgcetrizine hydrochloride for a period of 4 to 6weeks has given good results.

Pityriasis alba

This a type of non-specific dermatitis that

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characteristically produces hypopigmentedpatches most commonly on the face of atopicchildren. The patches show very fine scales andtend to disappear and reappear. Althoughregarded as a manifestation of atopic dermatitis,it is certainly not confined only to atopics. Lesscommonly, the face is spread and there arescattered lessions on the trunk and limbs that thengive some diagnostic difficulty. Treatment isoften disappointing. Avoidance of frequentwashing with soap and water must be advised.Today’s trend is towards treating pityriasis albawith topical mometasone furoate (0.1%) withexcellent results.

Diaper dermatitis

Diaper dermatitis or napkin rash is amultifactorial disorder. No single agent isresponsible for its cause even in a single patient.Participating factors include irritation fromprolonged contact with moisture from urine andfaeces, ammonia from diapers, loss of normalskin acidity and microbial colonization. Children,two to four months old are usually affected, withthose having an atopic or seborrhoeic backgroundbeing even more susceptible. Diaper dermatitistends to spare the creases and demonstraes asmooth erythematous involvement or a scaly andexudative reaction over the convexities of thethighs, pubis and buttocks. The present ofsatellite lesions indicates a yeast infection.Topical corticosteroids are helpful in thetreatment, and are indicated in all but the mildestcases. There is, however, virtually never any needto use applications containing more than 1%hydrocortisone. Twice daily application ispresently advocated. Fears that corticosteroidmight interfere with the descent of testes in boyshave not been confirmed, but the possibilityremains that such a problem could arise in lowbirth weight babies.

Lichen planus

Lichen planus is not an uncommoncondition. It typically presents wiht itchy flat-topped violaceous papules on the flexural aspectsof the wrists, about the ankles, and over the malegenitalia. Oral mucosal involvement may occureither alone, as a lacy network on the buccalmucosa, or in combination with skin lesions.Intolerable itching is the hallmark of lichenplanus. Oral lesions may ulcerate and cause painand dysphagia. Although nearly 70% of casesresolve spontaneously within 12 to 15 months,even in the best of circumstances lichen planusis not an easy disease to treat. Doubly so is lichenplanus in children. Tpoical steroids remain thesheet anchor in the treatment. But the problemsin lichen planus therapy is that proven medicinesare not safe and safer medicines are not proven.For instance the choice of topical steroids is verysignificant. A potent steroid like clobetasol mayprove to be dangerous and suppress the HPA axisby percutaneous absorption. More recently 0.1%mometasone furoate has proved to be as safe asand more effective than 1% hydrocortisone.

Conclusion

Any childhood dermatosis confounds andhumbles even the most experienceddermatologist in practice. The problem is not somuch as lack of effective therapeutic modalitiesbut the efficiency, dependability, and safetyprofile of such treatment in children. The criticalquestion every clinician finds addressing himselfis: what shall I prescribe for this child and how?To end, it is worthwile remembering that“behind the towering spires of medical knowledge,therapy sits as a small cottage.... yet, it is to thiscottage of therapy that the patient most wants tocome”, and how hard and difficult indeed the roadto this cottage is for the tender-footed littlechildren.


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THE BLADDER AND A GENERALAPPROACH TO IMAGING

* Vijayalakshmi G * Natarajan B

** Ramalingam A

The ultrasound picture that a clinicanreceives cannot be read like the plain X-ray orCT films that accompany a report. The sonologisthas studied the patient in many planes - sagital,coronal, axial and oblique - and then has givenrepresentative sections. so the operator wouldhave seen much more than the pictures he hassent.

One of the common films that accompaniesthe report is a cross-section of the bladder takenimmediately above the symphysis pubis. Fig.1shows the normal bladder. The contents of thebladder are normally black or anechoic. This is afeature of any fluid in the body-bile in the gallbladder, blood in the vessels or fluid collectionin any space. Now try to read Fig.2. There arewhite specks within the bladder. This is anabnormal finding. It is due to minute particulatematter because of pus or blood. Fig.3a showssomething very common that you all must befamiliar, which is a vesical calculus. This is seenas a white or echogenic focus. Calcification andbone also appear like this. Deep to this focus isseen a dark aftershadow. This is the hallmark ofa calculus. It appears because bone or calcium

RADIOLOGIST TALKS TO YOU

* Addl. Professor in Pediatrics** Addl. Professor in Radiology

Department of RadiologyInstitute of Child Health and Hospital forChildren, Egmore, Chennai

or metallic elements block ultrasound completely,Clots or debris, though white, do not cause anaftershadow.

Remember that every investigation has itsown pitfalls. Look at Fig.4. Here also you cansee a white focus behind the bladder. Is this acalculus? No. This is rectal air behind thebladder. How do you decide? When the patientis turned to a lateral decubitus position thecalculus also moves to the dependent wall(Fig.3b) while the air in the rectum remains inthe same position. This brings us to theappearance of gas in ultrasound. Air or gasappears white as it reflects all the sound wavescompletely so that nothing is seen deep to it. Thisis why ultrasound has not found much us in theevaluation of the chest unless it is filled with massor fluid. Air is white and also casts anaftershadow, but this does not have the sharp edgeof the acoustic shadow of the calculus.

After examining the contents of the bladderlook at the wall. Does it show any asymmetry inshape or indentation due to a lesion in theneighbourhood? (Fig.5). Now look at thethickness of the wall. It should be regular oruniform. Mild thickening is seen in cystitis. Fig.6shows a grossly thickened bladder wall in a caseof severe proliferative cystitis. The bladder wallis also thickened in case of posterior urethralvalves. So check for the presence of dilatation ofureters and the pelvicalyceal system which isalmost always present in this condition. Cystitisis rarely associated with uretero hydronephrosisand even then it is only mild.

Fig. 7 shows irregular thickening of thebladder wall with a large polypoidal mass

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Fig 1 - Normal bladder

Fig 2 - Turbidity of bladder contents


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Fig 3a - Vesical calculus Fig. 3b - Decubitus position. Where is the calculus now?

Fig 4 - Air in the rectum seen behind the bladder. See the aftershadow.

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Fig 5 - A lymph node indenting the left wall of the bladder

Fig 6 - Thickened bladder wall in case of severe proliferative cystitis.


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projecting inside from the right anterolateral wall.This is a case of rhabdomyosarcoma of thebladder. So, following the same concept asclinical examination, identify the shape, size,

Fig 7 - Rhabdomyosarcoma-bladder.

contour and contents of any lesion or fluid space,This will help you to assess the type and severityof the existing pathology.

CONGRATUATIONS

Dr. H. Paramesh MD, FAAP, FIAP, FIAMs., has been awarded fellowship (FIAA) by theIndian Academy of Allergy for his contribution to allergic diseases in India and Growth of Academy,during the National Conference in Pune between 28th - 30th November, 2002.

CONTRIBUTORS TO CORPUS FUND OF IJPP

Rs. 1000/-

Dr. Pranab Kumar Pati, Burdwan, West Bengal Dr. S.K. Bhavsar, Nasik., Maharashtra

Dr. M. Chinnasamy, Erode, Tamilnadu Dr. S. Yamuna, Chennai, Tamilnadu

Dr. K. Srinivas, Chennai, Tamilnadu

2003;5(1):71

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METATROPIC DYSPLASIA

* Raveendranath S** Ravisekar CV

** Venkataraman P*** Vasantha Mallika TK

**** Elizabeth John

Metatropic Dysplasia is rare skeletaldysplasia characterised by a non-lethal type ofcongenital dwarfism with a typical skeletaldysplasia (micromelia), joint changes with orwithout a tail like skin appendage over the sacralregion.

Case report

A 12 years old boy, 1st born of anonconsanguinous parentage presented with ahistory of multiple symmetrical joint swellinginvolving both small and larger joints. There wasno history of joint pain, fever, weight loss or skinrashes, or similar history in family members. Onexamination, he was undernourished with GradeII PEM, short statured (less than 5th percentile),normal intelligence and facial appearance. Patientwas having brachydactyly with fusiform swellinginvolving all interphalangeal joints with restrictedmovements and exaggerated lumbar lordorsis.Systemic examination including cardiovascularsystem was normal.

Investigations revealed a serum calcium of

CASE STUDY

* PG Student** Asst. Prof. of Pediatrics

*** Readers of Pediatrics**** Prof. of Radiology

Institute of Child Health & Hospital forChildren, Chennai.

9.8mg%, phosphorous 4 mg% serum alkalinephosphatase of 10 KA unit and ESR-10/20mm,Skeletal survey showed normal skull,platyspondyly of the cervical spine and elongationof AP diameter of the dorsolumbar vertebral body.Rest of the thorax was normal and the pelvisshowed a small square ilia with an anteriorsuperior iliac spine apparently more inferiorlyplaced than in normal. Long bones were showingdiaphyseal constriction and widely flaringmetaphysis. With this radiological findingdiagnosis of metatropic dysplasia was made.

Discussion

Metatropic dysplasia is a geneticallyinherited skeletal dysplasia with geneticheterogenicity with a prevalence rate of one inone million population. This conditions was firstdescribed by Moroteaux, Spranger andWiedemann. The term metatropic was selectedto indicate the change in body proportion perculiarto this condition, that occur with passage of time.

Fig 1. Showing multiple symmetrical jointswelling


72

At birth limbs appear short in relation to the trunkand hence a diagnosis of achondroplasia is madeat birth, eventhough the total body length is usuallynormal. By early childhood the trunk becomesshortened because of kyphoscoliosis and the limbsappear disproportinately long. This general habituslook like Morquio’s syndrome. At all time the headand face are normal. The thorax is normal andundergo progressive deformity includingprojection of the sternum, this at later stage leadsto cardio-respiratory problem. Stature showsmarked reduction with disproportionately shortlimb, reaches adult height between 110 and120cm. Skin tag (tail-like) appendage may beseen over the sacral region.

Blood and biochemical investigations arenormal. Radiological features and diagnostic inthis condition. Normal skull with cervical spineshowing platyspondyly and sometimes absenceor hypoplasia of the odontoid peg. Thoracic andlumbar spine in neonate shows earlyplatyspondyly, subseqnetly the appearance isvariable with diamond shaped vertebra (or) witha hump superiorly, with irregular ossificiation ofthe end plate and finally mild platyspondyly withelongation of AP diameter of the vertebra.Thorax in neonate shows short ribs withwidening of the costochondral junction. Pelvis

shows small square ilia with anterior superior iliacspine apparently more inferiorly placed than innormal with small sciatic notch and widenedpubic symphysis. Diaphyseal constriction andwidely flaring metaphyses in long bones, withdeep intercondylar notches in knee joints. Mostpatients with this disorder die in early infancyfrom respiratory insufficiency and at a later agefrom cardio respiratory problem associated withthe spinal and thoracic deformity. Secondaryosteoarthritis develop following the disorderedepiphyseal growth. Treatment is onlysymptomatic and supportive. The prognosis isguarded due to cardio-respiratory problems.

Bibliography1. Maroteax P, Spranger J, Wiedemann HR Arch

Kinderhalikal 1966; 173:211-226.2. Jenkin P, Smith MB, Kekinnell JS Metatropic

dwarfism, Brit J of Radiol 1970; 43:561.3. Rimonin DL, Sigger DC, Lachmen RS, Silberberg

R, Metatropic dwarfism, Kniest syndrome andthe pseudoachondroplastic sysplacia clinicalorthopaedics 1976; 114:70-82.

4. Etesan DT, Adomian GE, Ornoy, Koide T,Galabro A, Lungarottis, Lachman RS, RimoninDL 1984 Fibrochondrogenesis, Radiological andhistologic studies, Amercian Journal of MedicalGenetics. 1984:19;277-290.

5. Caffey’s Pediatric Radiology Text Book, 1586-1588.

REQUEST

Due to escalating cost of publications, all the life subscribers who had enrolled with onlyRs.500/- are requested to kindly give us a contribution of Rs. 1000/- (Rupees one thousand only).Those who have enrolled with Rs. 1000/- as life membership fee are requested to contributeRs.500/- (Rupees Five hundred only). The cheque / draft can be drawn in favour of‘Indian Journal of Practical Pediatrics’ payable at Chennai and send it to the Managing Editor,Indian Journal of Practical Pediatrics, IAP-TNSC Flat, Halls Towers, 56, Halls Road, Egmore,Chennai - 600 008. INDIA.

- Editorial Board

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CROUZON’S SYNDROME

* Archana B Patal** Ramesh L Renge

Crouzon’s syndrome is an autosomaldominant condition with craniosynostosis andfacial anomalies1,2. It has a wide range ofexpression and penetrance1. A fourth of thesecases do not have a family history and are newmutations3. Following is a case report ofmonozygotic twins with Crouzon’s syndrome.

Case report

3½ year old monozygotic twins of nonconsanguineous marriage presented withconvulsions and craniofacial dysostosis. Theywere born by caesarian section and their motherdied of eclampsia a day later. Grandmothernoticed flat occiput, small anterior fontanella andabnromal shape of skull of both the badies butdid not seek medical attention. The parents orsibs did not have similar features.

They first reported to the hospital at the ageof 9 months with generalized tonic clonicconvulsions, which was their 2nd Episode, the firsthaving occureed at the age of 2 months. The X-ray skull at this age showed sutural closure only(Fig.1). The fundus was normal. They weretreated with carbamazepine and weresubsequently free of seizures. There was nodevelopmental delay. Parents did not reportvision or hearing defect.

CASE STUDY

* Associate Professor** Lecturer

Dept. of Pediatrics,Indira Gandhi Medical College, Nagpur.

The twins reported again at the age of 3½years. They had tower shaped skull, frontalbossing, shallow orbits, ocular proptosis and ridgingof sutures (Fig.2). The palate was high archedand nose was beak like. Phenotypically the twinswere identical with similar blood groups. Fundusexamination of both the children revealedpapilloedema with blurring of margins and paledisc. The x-ray skull at this age showedcraniostenosis and silver beaten appearance(Fig.3). The CT scan relevaled diffuseeffancement of ventricular system, subtotalobliteration of subarachnoid space, scalloping ofinner table and fusion of all sutures except thelamboid (Fig.4).

Discussion

Total 58 syndromes with cranio synostosishave been described and limb findings are theprinciple distinguishing features1,4. Of all thecraniosynostosis, Crouzon’s syndrome accountsfor 3-7% of cases with a birth prevalence of 16.5/1,000,0005,6. Crouzon’s syndrome is a craniofaciosynostosis characterized by brachycephaly,ocular proptosis, maxillary retuusion, mid facialhypoplasia due to abnormal development and

Fig 1. X-ray skull showing sutural closure


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premature fusion of any or all cranial sutures,most frequently coronal7. In 1912, Crouzon forthe first time described it in a 29 years old motherand her 3 years old son8.

Crouzon’s syndrome manifests with facialdysmorphism in the form of hypertelorism,beaked nose, cleft, high arched palate (invertedv shaped), dental malocclusion1,9. In addition toabnormal facies they can have complications likeincreased susceptibility to middle ear infectionand conductive hearing loss due to atresia ofexternal auditory meatus and progressive visualloss due to raised intracranial tension1,9. Mentalretardation may also be present in 10-30%10.Occasionally CNS, spinal and congenitalmalformations are associated11,12. Because thesechildren did not receive any intervention they

Fig 2. Twins showing tower shaped skull,frontal bossing and propotosis

Fig 3. X-ray skull showing craniostenosis,silver beaten appearance.

manifested with signs of raised intracranial tension(silver beaten appearance on X-ray skull) andoptic atrophy on fundoscopy.

It has an autosomal dominant inheritance ofwhich 65% are familial, the rest (35%) representsporadic new mutations3. Mutations in the genecoding for fibroblast growth factor receptor 2(FGFR2) are the cause of the syndrome3. Amongmonozygotic twins, 71% twins are reported to beconcordant for oxycephaly (tower shaped)1,13.There are few reports of Crouzon’s syndrome intwins2,13,14,15,16,17,18. We present monozygotic twinsin which both are having identical features ofCrouzon’s. Unexpectedly there have been casesof monozygotic twins with differences inmanifestation of the syndrome. Singh M (1983)reported Crouzon’s in one of monozygotictwins where her counterpart was unaffected13.Lajeunie E, et al described monozygotic twinswith Crouzon’s syndrome in which one washaving thumb duplication as an additionalcongenital anomaly14. The discordance betweenmonozygotic pairs has been ascribed todifferences in placental vascular supply andallocation of unequal number of cells due toabnormal separation of fertilized embryo14.

Patients with Crouzon’s syndrome are to bemanaged with 3 primary goals of prevention ofFig 4. CT scan showing scalloping of inner

table

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increased intracranial pressure, prevention ofconstriction of brain growth and improvementof skull and facial appearance9. To be affective,craniotomy must be considered early in life,preferably during first 6 months of life19. Surgeryhalts the mental regression, lowers theintracranial pressure and most importantlyprevents vision impairment19. It does not preventdevelopment of mid face hypoplasia and does notimprove IQ once it is already impaired19.Therefore early intervention needs emphasis. Itconsists of linear craniectomy along theobliterated sutures or parallel to it in case ofsagital suture20. Polyethylene or tantalum stripsare placed along the bone edge to preventrecalcification and bridging20. The proceduremay have to be repeated if bone bridges crossthe suture lines early9. Hydrocephalus needsshunt surgery. Facial appearance can be modifiedby mid face advancement19.

Although Crouzon’s syndrome is anautosomal dominant condition, sporadicmutations may occur as in this case where therewas no family history. This mutation in the genecoding for FGFR2 occurred in the same embryothat cleaved to form monozygotic twins withidentical phenotypic representation of Crouzonsyndrome.

Crouzon’s syndrome can be diagnosedantenatally by chorionic villous biopsy (11weeks) and by searching for mutations in FGFR2gene using PCR for amplification and singlestrand confirmation polymorphism analysiswhich detects abnormal coding sequence andsplice junctions3,7. In the second trimesterbinocular and inter orbital diametermeasurements are useful to detect this syndrome.

References

1. Witt DR, Hall JG. Multiple congenital anomalysyndromes In: Rudolph’s Pediatrics, 20th edn.

Eds Rudolph AM, Hoffman JIE, Rudolph CD,Prince Hall int. Inc. London, 1996;p403.

2. Yasuda S, Enomoto T, Yamada Y, Nose T, IwasakiN. Crouzon disease associated with si-nus pericranii: a report on identical twin sisters.Childs Nerv Syst Apr 1993;9(2):119-122.

3. Reardon W, Winter RM, Rutland P, Pulleyn LJ,Jones B, Malcolm S. Mutations in the fibroblastgrowth factor receptor 2 gene cause Crouzonsyndrome. Nat Genet 1994;8:98-103.

4. Cohen MM Jr, Fraser FC, Gorlin RF. Craniofa-cial disorders. In. Principles and practical ofMedical Genetics. Vol 1. Eds Amery AEH, RimoinDL New York, Churchill Livingstone, 1990;p115.

5. Hunter AGW, Rudd ML. Craniosynostosis: Itsfamiliar characteristics and associated clinicalfinding in 109 parents lacking bilaterialpolysyndactyly or syndactyly. Tetralogy1977;15:301-310.

6. Cohen MM Jr, Kreiborg S. Birth prevalencestudies of the Crouzon syndrome: Comparisonof direct and indirect methods. Clin Genet1992;41(1):12-15.

7. Schwaltz M, Kreiborg S, Skovoy F. First trimes-ter prenatal diagnosis of Crouzon syndrome.Prenat Diagn Feb 1996; 16(2):155-158.

8. Crouzon O: Dysostose cranio faciale hereditaire.Bull et mem Soc Med Hop Paris 1912;33:545.

9. Lemieux BG, Wright FS, Swamian KF. Geneticand confenital Structural defects of the brain andspinal cord. In the practice of pediatric neurol-ogy. 2nd edn. Eds Swaiman KF, Wright FH, C.V.Mosby Co, St. Louis, 1982; 437-441.

10. Cohen MM. Craniosynostosis and syndromeswith craniosynostosis: Incidence, genetics, pen-etrance, variability and new syndrome updating.Birth defects (Original article seres) 1979;1513-63.

11. Anderson PJ, Hall C, Envas RD, Harkness WJ,Hayward RD, Jones BM. The cervical spine inCrouzon syndrome. Spine Feb 15, 1997;22(4):402-405.

12. Cinalli G, Renier D, Sebag G, Sainte-Rose C,Arnaud E, Pierre-Kahn A. Chiari malformationin Crouzon syndrome. Arch Pediatr 1996;3(5):433-439.


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13. Singh M, Hadi, F Aram GN, Arya LS. Cranio-synostosis-Crouzon’s Disease and Apert Syn-drome. Indian Pediatr 1983; 20(8):608-612.

14. Lajeunie E, Nonaventure J, EI Ghouzzi V, CatalaM, Renier D. Monozygotic twins with Crouzonsyndrome; concordance for craniosynostosisand discordance for thumb duplication. Am JMed Genet 2000 91(2):159-160.

15. David DJ, Cooter RD, Edwards TJ. Crouzontwins with clover leaf skull malformations. J.Craniofac Surg 1991 2(2):56-60.

16. Loffredo A, Sammartino A, de Crecchio G.Crouzon disease in twins, Clinical and patho-logical contribution. Ophthalmologica1977;175(6):297-304.

17. Keith J, Banik ND, Falkner F. Identical twinswith craniosynostosis of the sagital sutures.Indian J Pediatr 1968 35(44): 229-231.

18. Tatarelli R. A case of monozygotic twins withcraniostenosis. Ann Med Nav 1970 75(5):545-550.

19. Renier D, Marchac D. Craniofacial surgery forcraniosynostosis: Functional and morphologicalresults. Ann Acad Med Singapore 1988; 17(3):415-426.

20. Etheridge Jr JE. Birth defects and developmen-tal disorders, In. Pediatric neurology, 3rd edn.Eds Farmer TW, Harper and ROW, Philadelphia.1983; 77-80.

FORM IV

(see rule8)

1. Place of Publication : Chennai2. Periodicity : Once in 3 months3. Printer’s Name, Address : Mr. D. Ramanthan,

Alamu Printing works,5 Iyah Mudali street, Chennai - 600 014

4. Publisher’s Name : Dr. A. BalachandranNationality : IndianAddress : “F” Block, No. 177, Plot No.235, 4th Street,

Anna Nagar East, Chennai - 600 012.5. Editor’s Name, Nationality, Address : As above6. Name and Addresses of individuals : This journal is owned by the Indian

who own the news paper, Partners Academy of Pediatrics, IJPP office,and/or shareholders holding more Halls Towers, F-Block, Ground Floor,than one precent of the total No.33, Halls Road, Egmore, Chennai - 8capacity

I, Dr. A. Balachandran, hereby declare that the particulars given above are true to the best of myknowledge and belief.

Place: Chennai - 600 008. Dr. A. BALACHANDRANDate:1.04.2002 (Signature of Publisher)

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SCHIZENCEPHALY - A CASEREPORT

* Geethanjali M** Anuradha K

Schizencephaly is one of the many disordersof cerebral contact development1. It may presentwith a range of symptoms, one of which couldbe hemiplegia. Childhood hemiplegia, most oftenis caused by hypoxic vascular insults, infectionssuch as bacterial meningoencephalitis,hypercoagulable states or thromboembolicphenomena. Less often, space occupying lesionslike tuberculoma or malignancy could be thecause of stroke. A case of childhood hemiplegiacaused by schizencephaly, is presented in viewof its rarity and in order to highlight the fact that,it could be an uncommon cause of the commonlyencountered hemiplegia. The diagnostic value ofCT scan cranium in delineating the focalcerebral lesions is also emphasised.

Case report

A two and a half year old female child wasbrought to the out patient department with historyof weakness of the left upper and left lower limbsnoticed since the age of two years. This childwas born to non-consanguineous parents as fullterm normal delivery at home. Antenatal,intranatal and perinatal periods were uneventful.The developmental milestones were marginallydelayed. The weakness was heradlded by feverand first involved the left upper limb. Within aday, the child was found to drag her left foot while

CASE STUDY

* Associate Prof of Pediatrics** Reader in Pediatrics

Coimbatore Medical College & HospitalCoimbatore

walking. There were no seizures. There was nohistory of trauma to the head or antecedent oralsurgery, no history suggestive of cyanotic heartdisease, severe dehydration or contact withtuberculosis. Vision and hearing wereunaffected. The child was able to comprehendspeech and answer meaningfully with a fewwords.

On esamination, the child was conscious andoriented, there was no cyanosis or respiratorydistress; there were no neurocutaneous markers.No limb length discrepancy was observed. Thehead appeared small (head circumference: 42cmagainst the expected of 47.5cm). The child hadupper motor neuron type of facial palsy on theleft. Spasticity and weakness were present in theupper and left lower limbs; ipsilaterally, thedeep tendon reflexes were exaggerated andplantar response was extensor. The child walkedwith circumduction, the left arm held stiff. Therewere no involuntray movements cerebellar ormeningeal signs. The other systems wereclinically normal.

Fig 1. CT scan showing a cleft in the rightparietal lobe extending upto the ipsilateralventricle, communicating with it and causingdilatation by mass effect.


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Baseline investigations like complete bloodcount, x-ray chest, urine examination andscreening for tuberculosis were noncontributory.X-ray skull revealed microcephaly. CT scancranium revealed a cleft in the right parietal lobeextending from the cerebral convexity into theright lateral ventricle. There was ipsilateraldilatation of the posterior horn of the lateralventricle, suggesting schizencephaly of opentype. The child is undergoing regularphysiotherapy and is on periodic follow up.

Discussion

Schizencephaly, an anomaly of neuronalmigration is the result of an embryological insultoccurring during the critical period of braindevelopment2. It is characterized by theformation of unilateral or bilateral clefts in thecerebral hemispheres3. It is usually sporadic,rarely familial4. It usually presents between onemonth and ten years of age. It may rarelymanifest in the newborn period5. Few patientsremain asymptomatic lifelong. Vascular insult,genetic factors6, cytomegalovirus7 infection,trauma8 in mid pregnancy, amniocentesis8, latefetal exposure to warfarin9 have all beenimplicated in the pathogenesis. Associated

Fig 2. CT scan showing a cleft in the rightparietal lobe lined by hetorotopic grey matter.Mass effect on the ipsilateral ventricle is alsoseen.

anomalies10 may be, absent septum pulludicum,agenesis of corpus collosum, porencephalic cyst,septo optic dysplasia and holoprosencephaly.

The frequency of disorders of cerebralmigration is 0.5% of all cranial MRI studies11.In schizencephaly, there is an infolding of corticalgrey matter along a hemispherical cleft near theprimary cerebral fissures4. It may be of opentype (type II) or closed type (type I). The cleftmay be unilateral or bilateral1. The clinicalfeatures reported in literature include tetraparesis,hemiparesis10, epilepsy, developmental delay,mental retardation, head nodding12 and psychoticsymptoms3. The unilateral closed type has thebest neurological outcome1. Intractable seizuresand hydrocephalus usually complicate the opentype1. Language function is normal in unilateralschizencephaly1. Clefts are usually located in theparasagittal, parietal or temporal regions of thebrain13. Atypical features in this child are theabsence of seizures and the presence ofmicrocephaly instead of hydrocephalus.

Conclusion

Disorders of cerebral neuronal migrationhave a wide range of clinical manifestations.Although MRI is considered gold standard in thediagnosis14, CT cranium is very often a valuabletool in the precise dilineation of the site andnature of pathology, in most disorders of corticaldevelopment. Also, CT cranium is indispensablein the diagnostic armamentarium of any childpresenting with focal neurological deficit,because, it may spring a surprise many a time,regarding the ultimate diagnosis, as in this child.

Acknowledgement

We wish to record our sincere thanks toDr.B.Ramesh Babu, MD(Ped.) for his immensehelp in this venture. Our thanks are also due toDr.K.Palaniappan, MD, DCH., for his valuablesuggestions in drafting this manuscript.

2003;5(1):79

79

NEWS AND NOTES

APLS: The Pediatrics Emergency Medicine Course 22nd and 23rd March 2003

The Department of Pediatrics, Sir Ganga Ram Hospital, Delhi and Indian Academy of Pediat-rics, Delhi are organizing “APLS: The Pediatrics Emergency Medicine Course” as per guide-lines of Amercian College of Emergency Physician and Amercian Academy of Pediatrics.

The course will be conducted at Sri Ganga Ram Hospital, New Delhi by eminent faculty in thefield of pediatric emergency medicine.

The registration is restricted to 40 delegates on first come first serve basis.There is no sport registration.

The registration fee is Rs 1200/- (including course material) which may be sent by cheque/cash/bank draft in favour of “Ambulatory Pediatrics” to the Course Director, Dr. Suresh Gupta,Consultant, Pediatric Emergency Medicine, Department of Pediatrics, Sir Ganga Ram Hospi-tal, New Delhi 110 060.

Phone: 5152656, 5917591, 9810124391, Email: [email protected]

References

1. Packard AM, Miller VS et al, schizencephaly,Correlations of Clinical and radiological fea-tures, Neurology 1997 48(5); 1427-1434.

2. Tomas-Vila M, Garcia-Tamarit P et al,Schizencephaly associated with Porencephalyin a girl with Congenital Cytomegalovirus infec-tion, Rev Neurol 2000; 16, 31 (10), 952-955.

3. Alexander RC, Patkar AA et al, Schizencephalyassociated with Psychosis, J Neurol NeurosurgPsychiatry 1997 63 (3); 373-375.

4. Hilburger AC, Willis JK et al, FamilialSchizencephaly. Brain Dev 1993 15(3);234-236.

5. al-Alawi AM et al, Sporadic neonatalSchizencephaly associated with brain calcifica-tion. Ann Trop Pediatr 2001 21(1);34-37.

6. Denis D, Chateil JF et al, Schizencephaly: Clini-cal and imaging features in 30 infantile cases.Brain Dev, 2000; 22(8); 475-483.

7. Perez-Jimenz A, Colamaria V et al, Epilepsy anddisorders of cortical development in childrenwith congenital cytomegalovirus infection, Rev.neurol 1998; 26(149):42-49.

8. Mancini J. Lathel V et al. Brain injuries in earlyfetal life: consequences for brain development,Dev med child Neurol 2001; 43(1);52-55.

9. Pati S Helmbrecht GD, CongenitalSchizencephaly associated with in utero warfarinexposure Reprod Toxicol 1994; 8(2):115-120.

10. Amaral JG, yaraga RH et al, Schizencephaly: re-port of eleven cases, Arq Neuropsiquiant 200159(2-A): 244-249 (Article in Portuguese).

11. Jaw TS, Sheu Rs et al, Magnetic resonance im-ages of neuronal migration anomalies,Kaohsiung J Ned Sci 1998; 14(8):504-513.

12. Chiang LM, Huang SC et al, Ventriculo Perito-neal Shunt in the treatment of Schizencephalywith infantile spasm: report of one case,Zhonghua Min Guo Xiao Er Ke Yi Xue Hiu ZaZhi 1991; 32(4):257-261.

13. Leblanc R, Tanpieri D et al, Surgical treatmentof intractable epilepsy associated withSchizencephaly, Neurosurgery 1991;29(3):421-429.

14. Dubey AK, Gupta RK et al, SchizencephalyType 1. Indian Pediatr 2001; 38:1049-1052.


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Q. 1: Medical representatives are coming outwith Gatifloxacin. Can you please mention1. its use in pediatrics 2. its dosage and routesof administration 3. any specfic side effects?

Dr. J. Sheban,Kanyakumari, Tamilnadu.

A. 1. After a systematic search for the querryon Gatifloxacin, I have not come across anyauthentic literature or studies on Gatifloxacin inchildren. All the available studies pertain to thosein adults. I have gone through pub med medlinesearch. However my reply is as follows. Thesafety and efficacy of the Gatifloxacin is not yetestablished in children and hence presently thereare no valid indications for its use in pediatricpopulation. The drug has an expanded spectrumover ciprofloxacin and is recommended for usein adults for the treatment of acute exacerbationsof chronic bronchitis and treatment of communityacquired pneumonia.

Dr. Niranjan Shendurnikar,Asso. Prof. of Pediatrics,Medical College, Baroda,

Gujarat - 390 001..

Q. 2 How is a click produced?

(When a finger is pulled, a click may be heardat the metacarpo-carpal joint. But this click isnot produced again if the finger is pulled soon,once more)

Dr.Yashpaul,Jaipur

A. 2. Usually, the click is called “knucklecracking”. This phenomenon, “kuncklecracking” is due to mechanical subluxation of

QUESTIONS AND ANSWERS

the joint, with gas formation in the joint due tothe accompanying great decrease in intra articularpressure. The subsequent vaporization of jointfluid release enough free energy to produce anaudible “crack.” Once cracked, a knuckle cannotbe cracked again until the gas has been absorbedand increased space between the bone returnsto normal. This takes about 30 minutes.

Dr.Panchapakesa Rajendran,Professor and Head, Dept. of Rheumatology,,

Madras Medical College,Govt. General Hospital,

Chennai - 600 003.

Reference

Arthritis and Allied Conditions In: Text Book ofRheumatology, 12th Edn, Daniel J, Mc Carty, eds,1993; p.57.

Q. 3 What is the specific treatment of zoonoticdiseases caused by 1)Wolf 2)Fox 3)Dog 4) Rat5) Cat 6)Parrot 7) Lion 8) Cheetah 9) Monkey,Pet & Carnivorous, Herbivorous wild animals.

Q.4. Are Tetvac, anti rabies vaccine andsuturing of wound, necessary? If so, in whichtype of animal bites? What are the specificindications for tetvac, anti rabies vaccines? Catscratch disease is known to cause encephalitis.How do you differentiate encephalitis due toanimal bite and anti rabies vaccine? What isthe probable cause of the two?

Dr.B.C. Ramachandra,Harihar, Karnataka

A.3. The Zoonoses, collectively refers to diseasestransmitted by animals. These can be classified

2003;5(1):81

81

under: Bacterial, Fungal, Parasitic, Chlamydial,Rickettsial and Viral diseases. Hence specifictreatment depends on targeting the etiologicalagent and controlling of the transmitting vector

Note: For specific treatment refer to standard

treatment protocols of zoonoses management. Fordetails for other carnivorous and herbivorousanimal sources, kindly refer to zoonoses instandard books on zoonoses.A.4. Tet Vac is necessary in all animal bites

- antirabies treatment is indicated in bites bythe following: Dogs, Cats, Parrots, Bats,Snakes, Foxes, Woodchucks.Table 1. Zoonoses and treatment

S.No Name of the Diseases Caused Specific treatmentAnimals

1. Wolf Tetanus Anti Tetanus2. Fox Echinococcosis, Hydatid disease Albendazole 15mg/kg/day

Rabies, Tetanus (Max 80 mm.) x 1-6 MonthsAnti Rabies, Anti Tetanus

3. Dog Brucellosis (rarely), Campylo <8 yrs TMP - SMXbacteriasis, (Campylobacter Jejuni), > 8 yrs Doxycyline &Leptospirosis, Pasteurella, Multocida Rifampicin(Infrequently), Solmenellosis, Visceral Antidiarrheal, antipyriticlarva migrans, Ringworm, Yersiniosis etc.,(Rarely), Cutaneous larva migrans, Kindly refer to standardDog tape warm, Hydatid diseases, Rocky treatment protocols undermaintain spotted fever, rabies specific headings

4. Rat Leptospirosis, Rat bite fever, Typhus,Flea-borne endemic typhus (Rickettsia typhil)

5. Cat Bortenella henselae (Cat - scratchdisease), campylobacteriosis,Capnocytophaga, Canimorus (rarely),Pasteurella multocida, Plague,Solmenellosis, Tularemia, Yersiniosis,Ringworm, Sporotrichosis, Cutaneous larvamigrans, Dog tape worm (Dyphylidiumcaninum) Giardiasis, Toxoplasmosis,Visceral larva migrans, Rabies.

6. Parrot West Nile encephalitis/ Histoplasmosis7. Lion Not an animal sources for zoonosis8. Cheetah Not an animal source for zoonosis9. Monkey Tetanus, B virus (formerly herpes virus

simiae) by Macaque monkeys10. Rolents/Wild Plague, Relapsing fever, Tularemia

Rodents Ringworm, Q fever, Rocky mountain,Spotted fever, Colaradotick fever,California encephalitis, Hanta virusinfection, Lymphocytic choriomeningitis.


82

- Suturing of wound is generally avoided exceptin lacerated wounds involving face, scalp.Thorough cleaning with soap and water ismost important. No need for antisepticapplication.

- Viral Encephalitis following mosquito / tickbite through animal sources viz califormia(Wild rodents), Eastern equine (wild birds,poultry, houses), western equine (Wild birds,poultry, houses) St. Louis (Wild birds, poultry),Venezuelan equine (horses), Powassan(Rodents, rabbits) West Nile (Birds) havebeen recorded with specific manifestations.

- Encephalitis following ARV treatment hasnot been reported.

Dr. A. Parathasarathy,Retd. Senior Clinical Professor of Pediatrics

Madras Medical College, Chennai.

Reference and Bibliography

Amercian Academy of Pediatrics. Diseasestransmitted by animals. In: Pickering LK ed.2000 Red Book: Report of the Committee onInfections Disease. 25th ed. ELK Gnore VillageIL: Amercian Academy of Pediatrics; 2000:772-776.

Q.5. 1. What is the dose of inhaled salmeterol& formoterol and also oral deriphyllin retardtablets?

2. A 10 kg child is already on inhaledbudesonide 600mcg/day+oral deriphyllin 150mgretard. She is havign nocturnal cough withwheeze. How to manage her symptoms?

3. How long ketotifen can be given to childrenwith allergic rhinitis and atopy?

4. How long sodium cromoglycate andmonteleukast can be given for children withmild persistent asthma?

Dr.R.Ramakrishnan,Coimbatore, Tamilnadu,

A.5. 1. Formoterol and Salmeterol are longacting beta agonists used only by inhaled route.Their duration of action is about 12 hours.Salmeterol is a lipophilic molecule which has aslow onset but long duration of action (25mcgper puff, 2 puff bid or HS) whereas Formoterolbeing less lipophilic has fast onset of action andhas an equally long duration of action (12mcg perpuff, 2 puff bid or HS).

The oral dose of tab Deriphyllin ratard is10 mg/kg/dose q 12h. (Formulation is Tab 150

Table. 2. Comparison between formoterol, Salmeterol and Salbutamol

Variable Formoterol 24mcg Salmeterol 50mcg Sulbutamol 200mcgMean increase in specific 44 < 16 44airway conductance(SAW) at 1 minMaximum increase in 135 111 110SAW (time to) (2h) (2-4h) (30 min)Mean increase in SAW 56 58 ---at 12 hMaximum increase in 27 25 25FEV1 (time to) (2h) (3h) (30 min)Mean increase in 10 11 ---FEV1 at 12h

2003;5(1):83

83

NEWS AND NOTES

Meeting of the International Pediatric Transplant AssociationRio de Janeiro (Brazil) 5-9 April 2003

www.iptaonline.org

and 300mg). For Deriphyllin OD the dose is16-20 mg/kg/dose q 24 hours.

2. There are several issues which one will needto look into. First, check the compliance, (howfrequently is the canister purchased orconsumed, does it relate with recommended rateof usuage). Second, is the canister under usecontains medicine and functional. Third, checkthe inhalation technique. At this dose mypresumption is the patient is using MDI withspacer. Next, it may be pertinent to look for theother triggers and co-morbidities. Rule out GER,sinusitis etc. Look for any persistent triggers inthe child’s environment say environmentaltobacco smoke or a pet or mold/dampness in thehouse. If all this is fine, only then there is a needto alter the drugs. Most formulations of the longacting theophyllines become short acting if thetablet is broken or crushed. Therefore, it may bebetter to look for formulations which can bebroken or titrated e.g. Tab Theostan CR (scoredtables which can be broken into two) or spansulesof Duralyn. Should the child need further drugchange the options available to us are either addinga long acting beta agonist like Salmeterol orFormoterol or adding Leukotriene antagonists likeMontelukast or Zafirlukast before any further

increase in the inhaled corticostroids is done.

3. The drugs like Ketotifen if used for perennialallergy may need to be given for a very long term.However in this situation the preferred alternativemay be nasal topical sprays of steroids likebudesonide, mometasone etc. Ketotifen has norole in abolishing atopy and hence the drug shouldbe used selectively in the long term. The longterm use may be associated with occurrence ofobesity.

4. Treatment of persistent asthma requiresattempt at decreasing or withdrawing drug(s),after symptoms are fully controlled for 12 weeksor so. This is the general rule followed for inhaledconticosteroids. We in our practice attempt towithdraw Cromoglycate if the patient is totallyasymptomatic for a least 6 months. We havesafely used the drug for as long as 2-3 years insome patients. There is as yet limited experienceavailable for montelukast. However both thesedrugs do not require any tapering beforewithdrawal.

Dr. Varinder Singh,200, Dhadral Apartments,

Pitampura, New Delhi - 110 034.


84

BOOK REVIEW

Title : Fundamental of Pediatrics

Author : K.E. Elizabeth

Publisher : Paras Publishing, Hyderabad / Bangalore.

Constant updating of knowledge of pediatrics is essential for all practicing pediatricians.Undergraduate medical students also require a working knowledge of pediatrics, as Pediatrics is aseparate paper for them as per the guidelines of Indian Medical Council. Postgraudate students areconstantly on the lookout for textbooks which will improve their clinical skills and enhance theirperformance in examinations. ‘Fundamentals of pediatrics’ authored by Dr. K.E. Elizabeth meetsthe felt needs of the above three groups to a great extent.

The book is written in 23 chapters covering various aspects of pediatrics. The first chaptercomprehensively deals with history taking and physical examination including anthropometry. Thesubsequent chapters on growth and development, nutrition and immunization contain all the importantinformations on these subjects. In the chapters on fluid and electrolytes, neonatalogy, immunologyand infectious diseases, the author has included many practical aspects such as fluid and electrolytetherapy algorithms, neonatal resuscitation guidelines, graphic charts on phototherapy and exchangetransfusion indications, acute flaccid paralysis (AFP) surveillance programme and revised NationalTB control programme, to name a few.

The pragmatic approach of the author is evident in her emphasis on topics of greater relevanceto our country such as persistent diarrhoea and fulminant hepatitis in the chapter on Gastro Intestinalsystem, asthma management and postural therapy in the chapter on respiratory system and tetrologyof Fallot and rheumatic heart disease in the chapter on cardiovascular system. In all the chapters aworking knowledge on anatomy and physiology of that system along with relevant investigations isprovided first, followed by precise and recent information on various diseases. The chapter onneurology includes detailed clinical examination followed by description of common neurologicalproblems highlighting head injury, cerebral palsy and bladder dysfunction. State-of-art informationon gene therapy and human genome project are provided in the chapter on genetics. Various Nationalhealth programmes such as Baby FriendlyHospital Initiative (BFHI). Reproductive and child Health(RCH) programme and Integrated Management of Childhood Illness are discussed under communitypediatrics. This chapter has attempted to bridge the information gap in the minds of pediatriciansregarding many child health programmes and health indices. There is an unique chapter on curriculumof Pediatricis to guide the teachers and students to focus on particular topics.

The printing and layout of the book is excellent and the language is user friendly. Tables,algorithms and highlighting of important points is boxes are used appropriately and correction of afew spelling and formating errors in the subsequent editions will add to the reputation of this book.

Fundamentals of Pediatrics is a textbook, many learning and learned pediatricians will enjoyreading and get useful information.

2003;5(1):85

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PEDICON 2004

41st NATIONAL CONFERENCE OF THE INDIAN ACADEMY OF PEDIATRICS

Healthy child - Mighty IHealthy child - Mighty IHealthy child - Mighty IHealthy child - Mighty IHealthy child - Mighty Indiandiandiandiandia8-11 January 2004, Chennai

Venue: Sri Ramachandra Medical College & Deemed University,Porur, Chennai, Tamilnadu 600 116

The metropolitan city of Chennai known for its excellent hospitality and goodambience, invites you to the 41st National Conference of the Indian Academy of Pediatrics at SriRamachandra Medical College and Deemed University, Porur, Chennai between 8-11 January2004. The theme of the conference is “Healthy child - Mighty India”. The city of Chennai eagerlyawait to host this prestigious event after a span of 17 years by providing a veritable academic feastto fellow pediatricians.

Dr. C.S. Rex Sargunam Dr. A. Balachandran Dr. M.P. JeyapaulOrganising Chairman Organising Secretary Hon. Treasurer

Category Before Before Before Before Spot30.4.2003 30.08.2003 30.10.2003 30.11.2003

IAP Member Rs.2300 Rs.2800 Rs.3500 Rs.4500 Rs.5500Non IAP member Rs.2500 Rs.3000 Rs.3800 Rs.4800 Rs.6000Accomp. person Rs.2000 Rs.2500 Rs.3000 Rs.4000 Rs.4500PG Student # Rs.2000 Rs.2500 Rs.3000 Rs.4000 Rs.4500Senior citizen ## Rs.2000 Rs.2500 Rs.3000 Rs.4000 Rs.4500SAARC delegate Rs.2500 Rs.3000 Rs.3800 Rs.4800 Rs.6000Foreign delegate US $ 200 US $ 250 US $ 350 US $ 400 US $ 500Cancel/Refund * 70% 60% 50% 30% Nil

# PG student should submit the bonafide certificate## Senior citizen > 65 years* Refund will be done one month after the conference** Details regarding the preconference workshops (on 7.1.2004) will be intimated later

For further details contact:

Dr. A. Balachandran,Organising Secretary, PEDICON 2004,IAP - TNSC Flat, Ground Floor, F Blook, Halls Towers,33 Halls Raod, Egmore, Chennai 600 008. Tamil Nadu, IndiaPhone: 044-28190032, 28191524 Email: [email protected]


86

REGISTRATION FORM

41st NATIONAL CONFERENCE OF INDIAN ACADEMY OF PEDIATRICSPEDICON 2004

Healthy child - Mighty IHealthy child - Mighty IHealthy child - Mighty IHealthy child - Mighty IHealthy child - Mighty IndiandiandiandiandiaVenue: Sri Ramachandra Medical College & Deemed University, Porur, Chennai Tamil naduDelegate’s Title [ ] Dr. [ ] Prof. [ ] Mr. [ ] Mrs. [ ] Ms. IAP MembershipName ......................................................................................................................................................Mailing address ......................................................................................................................................Building/ Institution Name, Flat/Room ..................................................................................................No. .........................................................................................................................................................Street Name ...........................................................................................................................................Locality / Suburb ...................................................................................................................................City / District .........................................................................................................................................State .................................................................... Pin-code................................................................Residence STD Code ......................................... Phone no. ..............................................................Clinic/Hospital STD Code .................................. Phone no. ..............................................................Fax No. ............................. Mobile No. ................................. Pager No...................................E-mail .....................................................................................................................................................Food Preference [ ] Vegetarian [ ] Non vegetarian CME : Yes / NoIAP Delegate Fees Rs. .....................................................Non-IAP Delegate Fees Rs. .....................................................PG Student Fees Rs. .....................................................Accompanying person Rs. .....................................................Others Rs. .....................................................Demand Draft Number............................... of ................................... Bank.....................................Branch dated ...............................Please Note: Signature* CME is free, however, prior registration is a must.* Please send your payment only by demand draft. Please do not send any cash by post. Please do

not use cheque for payment. Demand draft to be made in favour of “Pedicon 2004”, payable atChennai.

* Please mail the registration form along with the Demand Draft by registered post or by courier onlyto the following address.

Secretariat:Dr. A.Balachandran, Organizing Secretary, PEDICON 2004,

IAP-TNSC Flat, Ground Floor, F Block, Halls Towers, 33 Halls Road, Egmore,Chennai-600 008. Tamilnadu, India.

Phone: 28190032, 28191524, Email: [email protected]

2003;5(1):87

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INDIAN JOURNAL OF PRACTICAL PEDIATRICSADVERTISEMENT TARIFF

Official Journal of the Indian Academy of Pediatrics - A quarterly medical journalcommitted to practical pediatric problems and management update

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Send your subscriptions, only by crossed demanddraft, drawn in favour of INDIAN JOURNAL OFPRACTICAL PEDIATRICS, Chennai and mailto: Dr. A. Balachandran, Editor-in-Chief, IndianJournal of Practical Pediatrics, “F” Block No. 177,Plot No. 235, 4th Street, Anna Nagar East,Chennai - 600 102

IJPP

2003;5(1):89

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JOURNAL COMMITTEE

Editor-in-ChiefDr. A.Balachandran

Executive EditorDr. D.Vijayasekaran

Managing EditorDr. K.NedunchelianAssociate Editors

Dr. N.C.GowrishankarDr. Malathi Sathiyasekaran

Dr. P.RamachandranDr. C.V.RavisekarDr. S.Thangavelu

Executive MembersDr. B.Anbumani

Dr. Janani ShankarDr. P.S.Muralidharan

Dr. K.NagarajuDr. T.L.Ratnakumari

Dr. T. RavikumarDr. S.Shanthi

Dr. So.ShivbalanDr. V.Sripathi

Dr. Nitin K.Shah(Ex-officio)

NATIONAL ADVISORY BOARD

President, IAP

Dr. H.P.S.Sachdev

President Elect, IAP

Dr.M.K.C.Nair

Editor, Indian Pediatrics

Dr. Panna Choudhury

Members

Dr. Ashok K.Rai

Dr. C.M.Chhajer

Dr. S.R.Keshava Murthy

Dr. Krishan Chugh

Dr. B.R.Nammalwar

Dr. A.Parthasarathy

Dr. M.Vijayakumar

Dr. Vijay N.Yewale

Indian Journal ofPractical Pediatrics

Subscription Journal of theIndian Academy of Pediatrics


90

President

Dr. H.P.S. Sachdev

President Elect

Dr. M.K.C.Nair

Imm. Past President

Dr. Dilip K.Mukherjee

Vice President

Dr. C.P.Bansal

Secretary General

Dr. Nitin K. Shah

Treasurer

Dr. Bharat R. Agarwal

Editor-in-Chief, IP

Dr. Panna Choudhury

Editor-in-Chief, IJPP

Dr. A. Balachandran

Joint Secretary

Dr. D.Vijayasekaran

IAP Team - 2003

Members of the Executive BoardDr. C.M.Aboobacker (Kerala)

Dr. Apurba Kumar Ghosh (West Bengal)Dr. Ashok Kumar Gupta (Jammu & Kashmir)

Dr. Ashok K.Rai (Uttar pradesh)Dr. Baldev S.Prajapati (Gujarat)

Dr C.P.Bansal (Madhya Pradesh)Dr. C.M. Chhajer (Tripura)

Dr. M.Dasaradha Rami Reddy (Andhra Pradesh)Dr. K.W.Deoras (Chhattisgarh)Dr. D.Gunasingh (Tamil Nadu)

Dr. S.R.Keshava Murthy (Karnataka)Dr. Krishan Chugh (Delhi)

Dr. Mahesh Kumar Goel (Uttar pradesh)Dr. Manoranjan Sahay (Jharkhand)

Dr. Niranjan Mohanty (Orissa)Dr. P.S.Patil (Maharashtra)

Dr. K.R.Ravindran (Tamil Nadu)Dr. Ramesh K.Yelsangikar (Karnataka)

Dr. Sailesh G.Gupta (Maharashtra)Dr. Satish V.Pandya (Gujarat)Dr. Shabina Ahmed (Assam)Dr.Shahshi B.P.Singh (Bihar)

Dr. S.C.Singhal (Haryana)Dr. B.K.Sudhindra (Kerala)

Dr. Sudesh K.Sharma (Punjab)Dr. Suil Gomber (Delhi)

Dr. Tapan Kumar Ghosh (West Bengal)Dr. Vijay N.Yewale (Maharashtra)

Dr. R.Virudhagiri (Tamil Nadu)Dr. Yashwant Patil (Maharashtra)

Indian Academyof Pediatrics

Kailash Darshan,Kennedy Bridge,

Mumbai - 400 007.

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