Child and Chest Health Care Delhi NCR

In the period of october 2021,both Dengue fever and Multi system inflammatory syndrome in children(MIS-C) are being seen in children in Delhi,India

Clinical and laboratory features are overlapping for both these diseases

It is important to differentiate between these as management entirely differs for both

In case of Dengue fever the cornerstone of management is aggressive fluid therapy with crystalloid and colloid with ionotrops if fluid therapy does not work and platelet transfusion if needed.

In cases of MIS-C, the cornerstone of management is steroids and IVIG(Immunoglobulins).Aggressive fluid management may be detrimental in cases of shock with cardiac dysfunction.

Fever are common in both but swellings of feet and hands,diarrhoea,conjuntival injections and altered sensorium along with the laboratory findings of hyperinflammation like highly raised CRP,Leukocytosis,raised D-Dimer are pointers towards MIS-C .In this situations,anti COVID antibody should be done and if positive ,confirms the diagnosis of MIS-C

If fever is associated with vomiting ,erythmatous rashes,myalgia along with the laboratory findings of leucopenia ,severe thrombocytopenia,hemoconcentration , raised serum ferritin level,it points towards the diagnosis of Dengue fever and NS1 antigen and or anti Den IgM should be done which when positive confirms the diagnosis of Dengue fever

In comparision to MIS-C,serum Ferritin level is higher in Dengue fever

References:

1. Ahmed M, Advani S, Moreira A, et al. Multisystem
inflammatory syndrome in children: A systematic review. E
Clin Med. 2020;26:100527.

2.Mishra S, Ramanathan R, Agarwalla SK. Clinical profile of
dengue fever in children: A study from southern Odisha,
India. Scientifica (Cairo). 2016;2016:6391594

3.Indian Pediatrics,volume 58,15 October,2021

Coronavirus (SARS-Cov 2) infections causing Coronavirus disease(Covid 19) have killed many people worldwide since its spread starting from November 2019.

Vaccines are now available worldwide to protect the world populations by synthesising antibody in human body which fights and kills Coronavirus when it enters into the body.

Vaccines are not recommended currently for pregnant women as well as for infants and children.

In such scenario, if it is known that coronavirus infections stimulate the production of antibody against it and it is transferred from mothers to newborn infants to protect them,it will be gift to infants by nature.

In childrens hospital Philadelphia,1714 women were studied who delivered between April 9 to August 8,2020.

Immunoglobulin G(IgG) were measured from the serum of mothers and cord blood of their newborns in 1471 cases

SARS-CoV 2 antibody IgG were detected in 83 women,that is in 6% women.This IgG is known to cross the placenta.

Among these 83 women,72 newborns were detected to have IgG,that is in 87% cases.

No antibody was detected in newborns of seronegative mothers.

In 11 newborns of seropositive mothers,no antibody was detected.Among them,5 mothers were having only IgM ,which does not cross the placenta and 6 mothers were having very low titre of IgG.

So, it is very important study,which showed the presence of protective antibody in newborns of mothers who were infected with Coronvirus and produced protective antibody for themselves as well as for their newborn infants.

REFERENCES:JAMA Pediatrics,Published online on January 29,2021

Tuberculosis is very very old disease of human .

There has been many research in the field of diagnosis and treatment of tuberculosis.

Inspite of all the efforts worldwide,it is still the killer disease due to various reasons responsible for the emergence of drug resistant TB (Tuberculosis).

Chief responsible factors for the increased incidence of tuberculosis are poverty leading to undernutrition, and HIV infection.

Main causes of emergence of drug resistance is not completing the prescribed regimen of treatment and high burden of tuberculosis.

TERMINOLOGIES BEING USED:

Monoresistant tuberculosis-Resistance of tuberculosis to any first line drug-Rifampicin,Isoniazid,pyrazinamide,ethambutol

Polyresistant tuberculosis: Resistance of tuberculosis to more than one drug but not to both Rifampicin and Isoniazid

Multi drug resistant(MDR) tuberculosis: Resistance to both Rifampicin and Isoniazid with or without resistance to other drugs

Pre-extensively drug resistant(PRE-XDR) tuberculosis:Resistance to both Rifampicin and isoniazid with resistance to either fluoroquinilones or second line injectables but not to both fluoroquinolones and second line injectables(SLI)

Extensively drug resistant tuberculosis(XDR):Resistance to Rifampicin,Isoniazid,fluoroquinolones and second line injectables(SLI)

RR-TB:Resistance to Rifampicin with or without resistance to other antituberculous drugs

SECOND LINE INJECTABLES(SLI):Amikacin,Kanamycin and capreomycin

PRIMARY RESISTANCE:When a child or adult becomes infected with drug resistant strain of Mycobacterium tuberculosis

SECONDARY/ACQUIRED RESISTANCE:This is more common.The individual is infected with drug sensitive strain of Mycobacterium tuberculosis but it becomes drug resistant during treatment due to selection of resistant mutant strain.The cause of such resistance is incopmlete or suboptimal treatmen

TERMS USED IN DIAGNOSTIC PROCESSES

C-Tb skin test;This is a new test for the detection of tuberculosis infection.In this test ESAT6/CFP10 antigens are used.It is done in the same way as Tuberculin skin test(TST).Antigen is injected intradermally on the forearm and reaction is read after 48-72 hours with the ball pen-scale method.An induration of 5mm is taken as positive irrespective of age,BCG status and whether with HIV or non HIV.The sensitivity is comparable to TST(MANTOUX TEST) and IGRA(QUANTIFERON GOLD)

IGRA(QUANTIFERON TB GOLD IN TUBE TEST;QFT-GIT: AND T-SPOT TB TEST:T-SPOT):This test is based on the principle of white blood cells of individuals infected with mycobacterium release interferon gamma when mixed with antigens derived from Mycobacterium.In this test whole blood is taken from individual and then mixed to ESAT6/CFP10 antigens and result is available within 24 hours.It does not differentiate between active and latent Tb.This test is not affected by BCG vaccination and is specific for Mycobacterium tuberculosis but not reliable below 5 years of age.

TESTS TO DETECT MYCOBACTERIUM:

LAMP;Loop mediated isothermal amplification test is 15% more sensitive than Zeil Neilson microscopy(smear microscopy) which is most widely used traditional test to detect Mycobacterium in smear preparation of sample in the form of sputum or gastric aspirate. It is temperature independent test ,done manually for amplification of DNA and can be read by naked eye with ultraviolate light.The report is available within one hour.WHO has recommended it as an alternative to ZN microscopy as it can be used in periphery

LED-FM:Light emitting diode fluorescent microscopy is 10 % more sensitive than ZN microscopy.With proper training it can be used in periphery although its specificity is less.WHO has recommended it as an alternative to ZN microscopy.According to WHO policy paper its sensitivity is 86.3%

CBNAAT :Cartridge based nucleic acid amplification test is based on polymerase chain reaction for the ampilification of DNA.Report is available within 2 hours.It can detect live as well as dead tuberculous bacilli ,so it can not be a replacement for smear microscopy and culture based drug sensitivity test for folllow up.It is also known as GenXpert /Rif test.It also detects Rifampicin resistance.Its sensitivity is 89% and specificity is 99%

GenXpert ultra(CBNAAT ULTRA):It is an advance version of GenXpert which is ultrasensitive with main difference from GenXpert is ,it can detect Mycobacterium from sputum even if the number of bacilli per ml is as low as 16,whereas in GenXpert ,the number of bacilli should be 131/ml for detection

TRUENAT;It has been developed in India by Molbio Diagnostics Pvt.Ltd.Goa.Its sensitivity and specificity to detect Mycobacteria and Rifampicin resistance is similar to CBNAAT/GenXpert test.But it requires 0.5 ml of sample as compared to CBNAAT which requires 1 ml.It is battery operated and not fully automated so it does not require continuous power supply and can be used in periphery

LPA-Line probe assay is based on polymerase chain reaction with reverse hybridization technique.First line assay detects resistance to isoniazid while second line LPA detects resistance to Fluoroqinolones and SLI.Report is available within 24-48 hours.According to recent RNTCP guideline,if Rifampicin resitance is detected on CBNAAT,second sample is sent to detect isoniazid resistance by LPA.If isoniazid resistance is detected,second line LPA is done for Fluoroquinolones and SLI.If Rifampicin sensitivity is detected on CBNAAT,sample is sent for LPA to detect isoniazid resistance.

According to WHO,END TB Programme,all patients should be subjected to DST(Drug sensitivity test) and the reference standard for this test is either liquid or solid culture.The report becomes available in 12 weeks.

To meet the requirement of universal DST as recommended by WHO,rapid tests are being developed as-NEXT GENERATION SEQUENCING(NGS).It is a rapid molecular test to detect mutations responsible for drug resistance.These are of 3 types

Targeted NGS-it sequences the specific point on gene of Mycobacterium tuberculosis

Whole genome sequencing(WGS)It sequences the whole genome ,so it is better than TNGS.

Pyrosequencing-it is method of sequencing by synthesis.

DRUGS TO TREAT RESISTANT TUBERCULOSIS:

GROUP-A-Levofloxacin or Moxifloxacin,Bedaquiline,Linezolid

GROUP-B-Clofazimine,Cycloserine or Teridizone

GROUP-C-Ethambutol,Delamanid,Pyrazinamide,Imipenam-cilastin or Meropenam,Amikacin or Streptomycin,Ethionamide or Prothionamide,Para-Aminosalicylic acid(PAS)

There are TWO regimens for the treatment of drug resistant tuberculosis,Long course and Short course

Long course is for 18-20 months-According to WHO 2019 guideline, 2 drugs from Group A except Bedaquiline in children,1-2 drug from Group B along with Delamanid must be chosen and the list of at least 5 drugs is completed from Group C.After 6 months of continuation phase,Delamanid is withdrawn and at least 4 drugs should be continued for the rest of the period of treatment..

DELAMANID CAN BE GIVEN TO CHILDREN ABOVE 3 YEARS OF AGE

SHORT COURSE REGIMEN:It is given for a period of 9-12 months.Usually the intensive phase is of 4-6 months consisting of Moxifloxacin,high dose isoniazid,ethambutol,,pyrazinamide,clofazimine,ethionamide or prothionamid,Kanamycin or Amikacin(7 drugs) followed by a fixed period of 5 months of Moxifloxacin,clofazimine,pyrazinamide and ethambutol(4 drugs)

Drug resistance to Fluoroquinolones and second line injectables should be ruled out before initiating short course treatment.

Now a days it is being emphasised and WHO in June 2020 has recommended ,all oral drug regimen where injectables shuold be replaced by Bedaquiline.FDA has approved Bedaquiline above 12 years of age but in India it has been approved above 18 years in accordance to RNTCP guideline.

NOTE:High dose isoniazid- dose is 15-20 mg/kg/day-it can cause optic and peripheral neuritis,ANA positivity,agranulocytosis,vasculitis and thrombocytopenia.

Linezolid-Dose 15 mg /kg od for wt<15 kg and 10-12 mg/kg od,for >15kg.It causes Myelosuppression,peripheral and optic neuritis and lactic acidosis.It penetrates CNS well

Ethionamide/Prothionamide causes hypothyroidism

EPTB and CNS Tb should be treated with longer regimen

REFERENCES:

TB facts.GenXpert Test-TB diagnosis,TB resistance testing,CBNAAT.2018.Available at:http://www.tbfacts.org/genexpert/Accessed

2019

World Health Organisation(WHO).The use of next generation sequencing technologies for The detection of mutations Associated with drug resistance in Mycobacterium toberculosis Complex;Technical guide.Available at http://apps.who.int/iris/handle/10665/27443.Accessesd2019.

World Health Organisation.WHO consolidated guideline on Drug Resistasnt tuberculosis treatment 2019?Available at :https:apps.who.int/iris/bitstream/handle/10665/311389/9789241550529-eng.pdf.Accessed 2019

Coronavirus 19 is a potential lethal virus causing Coronavirus disease 2019.

This disease has made realisation of its presence all over the world .

All age groups are being infected with this disease with varying morbidities and mortalities.

The disease has disrupted the educational and economic activities,all over the world.Schools are closed for a long time all over the world in the fear of spread of the disease among children and then in the household.

Researchers have studied 4130 cases through hospital surveillance network between 10,March 2020 to 10,April 2020.Among them 40 cases were children below 16 years of age.Household and parents were called for contact tracing .

It was observed that,in 79% of cases, the source were an adult in the household who were either diseased or infected prior to the infection in children.

In only 8% cases,children were primarily infected who then infected adults.

It was then concluded that,children, not only suffer from mild form of the disease in majority of cases,but they are also not the source of infection to othe children or adults in most of the cases.

The study was published in PEDIATRICS,the official journal of American Academy of Pediatrics.

In conclusion,there will be very little benefit from closing the schools, but it can adversely affects the academy of growing children.

REFERENCES:Pediatrics. 2020;146:e20201576, e2020004879

Pediatric tuberculosis is a burden to society and nation .

It is prevalent in every society and every nation.

It spreads by aerosols which comes in air after coughing by a diseased person and then inhaled by healthy person .

In children ,it is mostly contracted by a diseased adult suffering from pulmonary tuberculosis .

Lifetime risk for an infected child to become diseased is 10%.

CBNAAT-cartridge based nucleic acid amplification test, also known as GeneXpert test is now investigation of choice to detect Mycobacterium tuberculosis in children suspected to be suffering from tuberculosis .

The sensitivity of this test in sputum smear positive case is 98% and specificity is 99% but in smear negative and culture positive  cases its sensitivity is only 72% but specificity is 99%

In GA(gastric aspirate sample ) the sensitivity is only 68% in culture positive sample  and specificity is 99%.

Presently it is done on sputum, gastric aspirate ,CSF ,pleural fluid ,lymph done aspirate ,ascitic fluid,synovial fluid but  not on blood .

In lymph node aspirate,the positivity is 35%.

In some children,in which induced sputum and gastric aspirate are negative ,BALf,bronchoalveolar lavage fluid obtained by bronchoscopy has been found to be positive.

The sensitivity is  low in  Synovial fluid,pericardial fluid,ascitic fluid and very low in pleural fluid.

SO ,NEGATIVE TEST RESULT OF CBNAAT/GeneXpert TEST DOES NOT RULE OUT TUBERCULOSIS

Only one sample is needed and if unable to send the sample to lab immediately, it can be stored safely in refrigerator for 7 days but should not be freezed .

It is a real time PCR test and gives result in 2 hours.

It detects Mycobacterium tuberculosis as well as its resistance to Rifampicin.

If resistance to Rifampicin is detected and there is no suspicion of resistant tuberculosis clinically,then a fresh second sample is sent.

In second sample, if there is sensitivity to Rifampicin, it is labelled as Drug sensitive TB.

In GeneXpert Ultra test,second sample is not required.

The yeild is high in this test if there is chest X-ray findings suggestive of tuberculosis.

In case of only clinical suspicion with no radiological findings,the sensitivity is approximately 10%

SO,FOR THE HIGH YIELD,THIS TEST SHOULD BE SENT WHEN THERE IS SUSPICIOUS LESION ON CHEST X-RAY

In case of pleural effusion,the highest yield is from the examination of pleural biopsy which is positive in 80% cases.

The culture of pleural fluid is positive in only 10% of cases.

Other recommended tests are LPA-Line probe assay and LAMP-Loop mediated isothermal amplification.

These tests (CBNAAT,LPA annd LAMP)are called WRDT-WHO recommended rapid detection test.

The Gold standard diagnostic test is now, liquid culture in the form of MGIT-Mycobacterium growth indicator tube culture which gives result in 3 weeks.Previously it was solid culture.

Culture is positive in 1/3 to 1/2 cases of Tuberculosis.

FUTURE PROSPECT: CBNAAT has been used to detect Mycobacterium tuberculosis in stool sample  in children.Its sensitivity in one study in children and persons with HIV has been found to be over 80% and specificity over 95% when compared to respiratory sample.

After multicentre study,it may become the preferred sample for children in which respiratory sample is difficult to obtain.

TREATMENT:

Category II (CAT II) Treatment comprising of 2HRZES+1HRZE+5HRE has been completely withdrawn now.

There is  only one category now, for all patiens ,comprising of 2HRZE+4HRE,FIRST LINE ATT

For newly diagnosed cases,whether smear positive or smear negative this treatment should be completed for 6 months.

All patients,who have not taken ATT previously or have taken it for less than 4 weeks are labelled as New Case

In cases of neurotuberculosis or spinal tuberculosis,the continuation phase comprising of HRE should be extended for 8 months.

In cases of relapse,defaulters, retreatment,treatment after failure, and any contact with resistance tuberculosis,the sample should be sent for DST-Drug sensitivity test,  while the treatment started as 2HRZE+4HRE.

If the result comes as sensitive to first line medications,the treatment should be completed with this regimen only

If resistance comes to any drug, then the second line drugs should be started according to the sensitivity pattern.

Second line drugs are less potent and should be given for prolonged time.

Two highly potent drugs Dalaminid and Bedaquilline are now recommended for treatment of children with resistant tuberculosis.

Bedaquilline is recommended for children 6 years and above.

Dalaminid is recommended for children 3 years and above.

These two drugs are available at selected centres in India

In cases of LTBI -Latent tuberculosis bacillus infections,in which only Tuberculin sensitivity test or IGRA is positive but there is no clinical symptom and sign or any lesion in any organ suggestive of tuberculosis,no treatment is given in India.

In Western countries,the current recommendation is to treat LTBI with 12 Doses of HP-3HP-(3 months of HP)

Previously it was recommended for adults,but now it is recommended in children also

In such cases(LTBI),weekly doses of Rifapentine and isoniazid is given for 12 weeks.

Currently,it is not recommended for children below 2 years of age.

All children receiving isoniazid should be given daily dose of 10 mg of pyridoxine.

Definite indications of steroid along with ATT are TBM,Pericarditis,Addisons disease,Miliary TB with alveolocapillary block and TB uveitis.

Steroid can be given in endobronchial tuberculosis,pleurisy with severe distress,bronchial compression,mediatinal compression syndrome,laryngeal TB,and TB-IRIS(Immune reconstitution inflammatory sundrome).

Evidence is not sufficient for tuberculoma.

Prednisolone 1-2 mg/kg/day or dexamethasone 0.6mg/kg/day or any steroid in equivalent doses ,should be given for 4 weeks then tapered over next 4 weeks.

REFERENCES:

RNTCP Updated Pediatric TB Guidelines 2019 developed by Revised National TuberculosisControl Programme and Indian Academy of Pediatrics.

Guidance document draft as on 04.02.2019,Central TB division,Ministry of Health and Family Welfare,New Delhi India

CDC:Treatment Regimen for Latent TB infection

CDC:The 12 dose Regimen forLatent Tb infecvtion Treatment:Fact Sheet for clinicians

Eur Respir J 2019 53:1801832; published ahead of print 2018,
doi:10.1183/13993003.01832-2018

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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Faizan is a 12 years male child who was referred to us due to unmanageable fever with features of shock.

At our centre there was no fever ,the child had not passed urine in last 12 ours,pulse was not palpable and

blood pressure was 80/60mmhg,tongue was dry but not coated,chest clear on auscultation,CNS -NAD,P/A Liver 2cm and Spleen just palbable.

 

On exploring the history,the child was having fever off and on for last 6 weeks being treated by local doctor,with high fever for last 4 days ,pain abdomen for last 3 days and vomiting sensation but no vomiting with generalised body pain for last 2 days.

There was no history of cough,cold,loose stools,or burning urination.No H/O repeated ear discharge,repeated skin rashes,repeated headache or abnormal body movement with loss of conciousness.

he was involved in wrestling competition for last 1-2 years and I suspect he was taking some muscle making drugs in the form of steroids.His weight was 50 kg and was looking like an adult.

He was given intravenous normal saline boluses to treat the shock and blood was withdrawn for investigations.

He recovered from shock in next 24 hours without catacholamimnes,started to pass urine normally ,pulse became palpable with a rate of 72/m and Blood pressure 1oo/70mmhg then 110/80mmhg

He was carrying some investigations reports which was as under

Hb 17gm with hematocrit 51%

TLC 1100 with 80%polymorph

Platelet count 24000/cmm

Malaria antigen negative

We thought,we are dealing with dengue shock syndrome,then reports from our centre came which was as under

After 12 hours of starting treatment blood picture was as below

Hb 14gm/dl with hematicrit 42%,TLC 9000,with 80%polymorph

Platelet 32000/cmm

He was on treatment with IVF ,iv ondensatron and iv pantoprazole

After 7 hours blood count was repeated and report was as below

Hb 11gm,TLC 8000 with 80% polymorph

Platelet count 32000/cmm

At this time other reports came which was as under

S.BIL 0.9mg,SGPT 1300IU,SGOT1350IU

S.SODIUM 122MEQ/L,S.POTASSIUM 4.5MEQ/L,BLOOD UREA 56mh/dl.S.CREATININE 1.3mg/dl

S,\.ALBUMIN 3.4GM,S.GLOBULIN 4.2GM,A/G 0.8

SERUM WIDAL 1:160

DENGUE IGM NEGATIVE

DENGUE IGG POSITIVE

MALARIA ANTIGEN NEGATIVE

CHEST X-RAY NORMAL

USG ABDOMEN bilateral mild pleural effusion,withj mild ascites with edematous gall bladder wall

so, these were consistent with viral infection,probably with dengue virus with salmonella infection

We started iv ceftriaxone

After 15 hours blood picture was as below

Hb 8gm with hematocrit 25%,TLC 4000,

Platelet 22000/cmm

AT this I requested some special investigation .and previous investigation repeated after 36 hours and report was as below

SGPT 3500IU,SGOT 3700IU,

S.SODIUM 129MEQ/L,S.POTALOODSSIUM4.5MEQ/LS.CREATININE 1MG/DL,BLOOD UREA 34MG/DL

S.ALBUMIN 2.4GM.S.GLOBULIN 3GM/DL,A/G 0.8

Platelet count 22000/cmm

Now the child developed fever which was recorded 101degreeF

At this time 6 units platelets was transfused after giving oral paracetamol ,when fever came down.

Child was feeling better and started to take orally

There was no bleeding from any obvious site throught the illness

Platelet count was repeated after 2 hours of transfusion

and it was still 22000/cmm

NOW SPECIAL REPORTS CAME WHICH WAS AS UNDER

S.TRIGLYCERIDE 165MG/DL

S.CHOLESTEROL 126MG/DL

S.FERRITIN 12000ng/ml

At this time the child was diagnosed as a case of

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS (HLH) probably due to Dengue virus infection.

HLH is a condition of uncontrolled activation of macrophages and lymphocytes with storming release of cytokines leading to multiple organ damages and consequent clinical manifestations.

It is of two types:

PRIMARY HLH

SECONDARY HLH

Primary HLH is due to congenital defects leading to uncontrolled activation of macrophage and lYmphocytes,whereas secondary HLH is due to various infective and non infective conditions,leading to uncontrolled activation of macrophages and lymphocytes.

PATHOPHYSIOLOGY

Macrophages which are derived from monocyets act as a presenter of antigens to the     lymphocytes .

A subset of lymphocytes called NK cells (Natural killer cells) and CTL (cytotoxic T cells) are involved in  killing and washing out activated macrophages from blood cells pool when their work is over and are no more needed.If  NK cells and or CTL becomes less effective or  ineffective in number and function, either due to congenital or aquired cause,there will be uncontrolled increase in number of activated macrophages ,uncontrolled activation of lymphocytes and histiocytes and storm like release of cytokines.This is the reason,this condition is also called as macrophage activation syndrome.

Cytokines released are interleukin1,interleukon6,interleukin10,gamma interferon and tumor necrosis factor alpha with some others interleukin 2 soluble receptor(CD25)

These cytokines creats aggressive inflammation throughout the body and there is engulfment of blood cells like RBC,WBC and Platelets by activated macrophage,lymphocyte and histiocytes .This is why, the condition is known as hemophagocytic lymphohistiocytosis(HLH).This is condition of aggressive but ineffective immune response which ultimately damages multiple host organs.

Hemophagocytosed macrophages demonstration in bone marrow is not necesary to diagnose this condition and moreover it is not pathognomonic.

ETIOLOGY:

PRIMARY HLH : There are 5 types of genetic mutations known till date .PRF and SAP mutations are important among them.

SECONDARY HLH:Activated by infective and noninfective conditions.

Among infections, the common causes which may trigger HLH often in the setting of primary or secondary immunodeficiency are

Viral-Epstein-Barr virus,CMV,Dengue virus

Bacterial-Enteri Gram negative rods ,Staphylococcus,Streptococcus,Mycobacterium tuberculosis

Fungal-candida albicans

Parasitic-Leishmania donovani,Plasmodium

Ricketsial-coxiella burnetti

NON INFECTIVE CONDITIONS:

Primary immunodeficiency diseases,secondary immunodeficiency due to any cause, some malignancies like leukemia and lymphoma, autoimmune diseases like systemic onset juvenile idiopathic arthritis,systemic lupus erythmatosus

CLINICAL FEATURES:The primary HLH usually present in infancy but may present later on at any age.The secondary HLH depends on the age of onset of inciting diseases.The disease present with fever,malaise,irritability,restlessness,vomiting and some times with respiratory distress..On clinical examination,one may find pallor,icterus,generalised lymphadenopathy,splenomegaly,hepatosplenomegaly,generalised body rashes which may be maculopapular pruritic or morbilliform rashes,symptoms of CNS involvement similar to meningitis or acute demyelinating encephalomyelitis may be seen.

ON INVESTIGATION;BLOOD– common findings are anemia,pancytopania,hyperbilirubinemia,increased transaminases,hypoalbuminemia,persistent hyponatremia,hyperferritinemia usually >10000ng/ml,hypofibrogenemia,hypertriglyceridemia and decreased ESR

ON RADIOIMAGING:CXR may reveal bilateral pleural effusion and USG abdomen may reveal edematous gall bladder with its wall thickening and ascites.MRI brain may show hyperintensities in gray and white matter along with supratentorial and infratentorial regions.

DIAGNOSIS:It is established by either demonstration of genetic mutations consistent with HLH which is available at few selected centres worldwide or fulfilling 5 out of following 8 criteria

1.Fever of more than 5-7 days

2.Splenomegaly:palpable spleen in the left subcostal region

3.cytopenia(at least 2 cell line affected-Hb equal to or<9g/dl : equal to or <10gm/dl for neonates,platelet<100000/cc,neutrophil<1000/cc

4.Hypertriglyceridemia(equal to or>265mg/dl) and or hypofibrogenemia(equal to or<150mg/dl)

5.Hyperferritinemia(serum ferritin equal to or more than 500ng/ml)

6.Increased level of CD 25 in serum(equal to or more than 2400U/ml)

7.Decreased or absent NKcell (Natural Killer cell) activities)

8.Demonstration of hemophagocytosis in bone marrow,spleen or lymph nodes

Many times, less than 5 criteria are met and even then the diagnosis is made .Moreover,in upto 70% cases, the initial bone marrow examination does not show hemophagocytosis ,which may be found later on.

TREATMENT:For primary HLH ,when genetic mutation is established the current recommendations are

Etopocyde

corticosteroids

Intrathecal methotrexate

These should be given even in presence of pancytopenia.These treatments are given to calm down the hyperimmunologic response so as to lessen the organ damage.The definitive treatment is Allogenic Stem cell transplantation.

For secondary HLH , treatment is aimed at treating and controlling the underlying infective or noninfective conditions along with supportive care.If there is any evidence of iatrogenic immunosuppression,the immunosuppressive agents are withdrawn and underlying infections are treated along with supportive care. Most of the time, for non infective causes or no known or untreatable infections ,Etoposide remains the drug of choice.Other agents are interferon and intravenous immunoglobulin.Etoposide has cytotoxic effect on macrophages ,thus decreases cytokine production and hemophagocytosis,limiting the organ damages.

PROGNOSIS:For primary HLH the prognosis is invariably poor with certain fatality. Even after appropriate treatment the disease may be suppressed to again flare up after some time and death occurs. The only cure is Allogenic stem cell transplantation which is being done at certain centres in the world including India.

For secondary HLH ,the prognosis may be excellent if infection is the causative factor,it is timely diagnosed and appropriatley treated if treatable.. For non infective causative factors the prognosis is poor with very high mortality.

REFERENCES:

1.Stephan Ladisch,Hemophagocytic Lymphohistiocytosis volume 3,Nelson Textbook of Peditrics,20e,2016,2488-2489

2.[Guideline] Henter JI, Elinder G, Ost A. Diagnostic guidelines for hemophagocytic lymphohistiocytosis. The FHL Study Group of the Histiocyte Society. Semin Oncol. 1991 Feb. 18(1):29-33. [Medline].

3.Pal P, Giri PP, Ramanan AV. Dengue associated hemophagocytic lymphohistiocytosis: a case series. Indian Pediatr. 2014 Jun. 51(6):496-7. [Medline].

4.Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol. 2010 Jan. 6(1):137-54. [Medline].

5.http://www.uptodate.com/contents/clinical-features-and-diagnosis-of-hemophagocytic-lymphohistiocytosis/abstract/20