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Aug18
SCAPPING MCI,DCI & NCI-GOVERNMENT'S POLICY DESERVES CRITICISM
UPA II GOVERNMENT UNDER LEADERSHIP OF MR.GULAM NABI AZAD ,A VETERAN POLITICIAN AND CLOSE TO MRS.SONIA GANDHI IS CONTINUOSLY STRIKING NAILS AND NAILS IN THE COFFIN OF MEDICAL PROFESSION ,FIRST ROBBING THE AUTONOMY OF "MEDICAL COUNCIL OF INDIA" BY BRINGING AN ORDINANCE THROUGH THE OFFICE OF PRESIDENT THROGH MEETING IN COUNCIL OF MINISTERS AFTER ARREST OF MR.KETAN DESIA ,PRESIDENT OF MCI THROUGH CBI N THE CHARGE OF ACCEPTING BRIBARY FOR ISSUING NO OBJECTION CERTIFICATES TO FEW PRIVATE MEDICAL COLLEGE IN PUNJAB.
GOVERNMENT IS NOW SAYING THAT DR.KOHLI,PRESIDENT OF "DENTAL COUNCIL OF INDIA" AND MR.R.DILIP BABU.PRESIDENT OF "NUSING COUNCIL OF INDIA" ARE TOO ENGAGED IN MALPRACTICE AND HAVE EARNED HUGH MONEY,CBI IS SEEKING PERMISSION TO IVESTIGATE THESE FOLLOWS AND CENTRAL HEALTH MINISTER WILL BRING AN ORDINANCE EITHER IN THIS PARLIAMENT SESSION OF OTHERWISE THROUGH COUNCILOF MINISTER'S MEETING ORDINANCE THRROUGH PRESIDENT'S OFFICE TO SCRAPE AUTONOMY OF THESE TWO COUNCILS AS DONE TO MCI.
AS INDIAN CITIZEN,NO BODY IS INTERESTED TO PROTECT THE CULPRIT IF PRESIDENT OR VICE PRESIDENT OR FEW MEMBERS OF THESE COUNCILS HAVE DONE ANY CORRUPTION THEN THEY MUST BE PUNISHED BUT LIKE 'SEBI,COMMON WEALTH GAME OR BCCI OR IPL OR OYMPIC OR FOOTBALL ASSOCIATIONS,CULPRIT CORRUPT OFFICIALS SHOULD BE REMOVED NOT THE WHOLE AUTONOMOUS BODY IF SUCH ACTION IS BEING DONE THEN OUR PARLIAMENT SHOULD DISSOLVE ALL THESE AUTONOMOUS BODIES AND PARLIAMENTARY COMMITTIES ON DIFFEREN MATTERS AND MINSTERS AND BUREAUCRATS OF THESE MINISTRY SHOULD BE MADE INCHARGE OF EVERY SUCH BODY BUT WE KNOW THAT IN THIS CASE CORRUPTION WILL REACH TO PEAK AND EVERYTHING WILL BE A POLITICAL PARTY GAME AND MANY SCAMS WILL EMERGE AND HARDLY ANY POLITICIAL WILL BE PUNISHED AS COMMON PRACTISE IN OUR COUNTRY. THE REASON SUCH BODIES ARE UNDER CHARGE OF CORRUPTION BECAUSE THEY HAVE FEW PRESIDENT AND MEMBERS WHO ARE THERE FOR MANY YEARS BY BLESSING OF POLITICAL BOSSES ,MANY POLITICIANS WHO NEVER PLAY ARE HEAD OF SPORTS AUTHORITIES ,FEW DOCTORS ARE RUNNING THESE MEDICAL COUNCIL FOR YEARS,IT IS NEEDED THAT OUR PARLIAMENT SHOULD MAKE RULE THAT NO PRESIDENT OR MEMBER SHOULD BE IN THESE COUNCIL FOR MORE THAN 03 YRS EITHER REPRESENTATIVE OF CENTRAL GOVERNMENT OR STATE COUNCIL OR REPRESENTATIVE OF UNIVERSITY OR ELECTED FROM ANY OTHER ASSOCIATIONS,PRESENCE OF FEW SUCH CORRUPT PERSONS CANNOT BLAME THESE IMPORTANT AUTONOMOUS BODIES NEEDED VERY MUCH FOR SMOOTH RUNNING OF OUR MEDICAL AND HEALTH EDUCATION.FEW UNTRAINED IAS OFFICERS AND SENI OR OTHERWISE EDUCATED POLITICIANS CANOT JUSTICE WITH THESE AUTONOMOUS BODIES,MERE SELECTION OF FEW EXPERTS BY THESE PERSONS WILL BRING THEIR WELL WISHERS AND CATORIE PEOPLE AND DEMOCRACY WILL BE STRANGULATED IN THESE ORGANISATION AS IF WE READ BELOW PARAGRAPHS WE SHALL KNOW HOW WISELY THE CONSTITUTION OF THESE ORGANISATION HAS BEEN WRITTEN .
MEDICAL COUNCIL OF INDIA,DENTAL COUNCIL OF INDIA AND NURSING COUNCIL OF INDIA ARE STATUTORY BODIES TO REGULATE MEDICAL,DENTAL AND NURSING EDUCATION AND SERVICE IN THE COUNTRY.MEDICAL COUNCIL OF INDIA WAS ESTABLISHED IN YEAR 1934 UNDER MEDICAL COUNCIL OF INDIA ACT 1933,IT WAS AMENDED POST INDEPENDENCE IN 1956.IT WAS FURTHER AMENDED IN YEAR 1958,1964,1993,2001 AND 2004.iN YEAR 2009 'MCI' CELEBRATED ITS PLATINUM JUBLEE IN YEAR 2009.IN YEAR 2002 HON'BLE SUPREME COURT CONSTITUTED A BODY OF THREE EMINENT DOCTORS DR.TANDON, DR.MRS.KANTHA AND DR.RANGABHASYA TTO MONITOR FUNCTIONING OF MCI AND THEY SUGGESTED THAT MCI SHOULD BE EMPOWERED MORE AND MORE BUT STILL GOVERNMENT REJECTS MANY ITS PROPOSAL TO START NEW MEDICAL COLLEGES BECCAUSE AS PER 1956 ACT,GOVERNMENT ONLY CONSTITUTES AND REGULATE MCI BY MAKING RULES .GOVERNMENT NOMINATES ITS 37 MEMBERS DIRECTLY CAN CONSTITUTE ANY ENQUIRY IF MCI IS NOT WORKING PROPERLY,CENTRAL GOVERNMENT REGULATE POST GRADUATION COURSE DIRECTLY AND MCI CANNOT START ANY MEDICAL COLLEGE WITHOUT PERMISSION FROM GOVERNMENT.MCI FINANCE IS AUDITED BY CONTROLLER AND AUDITOR GENERAL OF INDIA AND WHOLE MCI IS UNDER SCAN OF PARLIAMENTARY COMMITTEE OF HEALTH AND FAMILY WELFARE.
ITH HAS GOT MEMBERS FROM MEDICAL PRACTITIONERS FROM ALL OVER INDIA REGISTERED IN STATE MEDICAL COUNCIL ,BESIDES MEMBERS FROM STATES AND UNIVERSITIES.PRESIDENT AND VICE PRESIDENTS ARE ELCTED,BUT IT HAS A SEPARATE JURISTIC PERSONALITY ,IT IS NOT A MERE MOUTH PIECE OF GOVERNMENT,GOVERNMENT CANOT INTERFEE DIRECTLY INITS AFFAIS,REMOVE OFFICE BEARERS AND GUIDE AND SUGGEST THEM UNDER PRESSURE ,THIS THE REAL PROBLEM OF MCI AND GOVERNMENT ,NO DOUBT ITS OFFICE BEARERS HAVE DONE SOME MISTAKES BY ON THIS BOARD FOR YEARS AND MANIPULATION GOVERNMENT THROGH BACKDOOR INFLUENCING AND EARNING HUGH MAKING SUCH BODIES AS THEIR CORPORATE HOUSES BUT HERE IS A FAULT OF BBOTH MCI AND GOVERNMENT WHY GOVERNMENT FOLLOWED THERIR RECOMMENDATION AND ALLOWED THEM AT THESE PLACES FOR YEARS.THIS ORDINANCE 2010 IS FOR ONE YEAR AND HAVE STARTED A FIVE MEMBER BOARD OF GOVERNORS TILL NEW COUNCIL IS ELECTED.THIS ORDINANCE ITSELF IS CONTOVERSIAL FOR A STATUTORY BODY LIKE MCI AS ITS PARENT LAW DOESNOT PERMIT FOR SUCH DISSOLUTION ,GOVERNMENT OF INDIA HAS INTRODUCED A BILL IN PARLIAMENT ON 3RD MAY2010 "NATIONAL ACCREDITATION ANDREGULATORY FOR HIGHER EDUCATION INSTITUTIONAL BILL 2010"UNDER WHICH IN MANY UNLAWFUL CONDITION GOVERNMENT CAN DISSOLVE ANY STATUTORY EDUCATION BODY AFETER GIVING ENOUGH TIME TO REPRESENT.PREVIOUSLY FORMER HEALTH MINISTER DR.A RAMDOSS ALSO WANTED TO DISSOLVE MCI THROUGH AN ORDINANCE BUT PMO SEND IT TO PARLIAMENTARY COMMITTEE WHO REJECTED IT.
GOVERNMENT 'S HRD MINISTRY HAS BROUGHT A BILL NAMED AS "NATIONAL COMMISSION FOR HIGHER EDUCATION(NCHER) AND WANT MEDICAL EDUCATION LIKE ALL EDUCATION UNDER IT BUT HEALTH MINISTRY HAS ADVOCATED 'NATIONAL COUNCIL FOR HUMAN RESOUCE AND HEALTH(NCHRH) TO RETAIN MEDICAL EDUCATION UNDER THIS MINISTRY ,THERFORE WE CAN ASSUME HOW TWO DEPARTMENTS/MINISTERS ARE FIGHTING TO KEEP THIS GOLD MINE UNDER ITS REGULATION AND HERE INTEREST OF MEDICAL EDUCATION,SERVICE AND STATUS WILL BE COMPROMISED AND POLITICIANS AND BUREACRATS WILL EARN IN CRORES DISSOLVING THESE COUNCILS .AS PAST PRESIDENT OF THESE BODIES MIGHT EARNED HUGH EDUCATION IS ON SALE FOR STARTING NEW MEDICAL COLLEGE AND DENTAL COLLEGES AND NURSING COLLEGES WHERE A STUDENT HAVE TO PAY LAKHS IN WHITE AND LAKHS IN BLACK TO GET ADMISSION UNDER DIFFERENT QUOTAS IN GRADUATE COURESE AND CRORES FOR POST GADUATION IF SUCH HIGH FEES ARE BLOCKED BY GOVERNMENT CORRUPTION WILL GO AWAY FRO MEDICAL COLLG OR DENTAL COLLEGE OR NURSING COLLEGE.EVEN VERY WEAK STUDENTS ARE ADMITTED EITHER AS SPECIAL OR NRI QUOTA AND THESE WEAK REMAIN WEAK FOR YEARS AS THEY ALSO GET THROUGH BY BRIBERY IN THESE PRIVATE MEDICAL COLLEGE,GOVERNMENT SHOULD STOP ALL THESE THINGS AND STOPS COPMLETE CAPITATION AND BACK DOOR ENTRY FEE BUT THESE WILL NOT BE STOPPED BY GOVERNMENT BECAUSE OTHERWISE HOW THESE POLITICIANS AND BUREAUCRATS WILL EARN CRORES OF RUPEES.
THERFORE IT IS NEEDED THAT THESE COUNCILS ARE NOT DISSOLVED BUT SHOULD BE MADE MORE ACCOUNTABLE,TRANSPARENT AND FUNCTIONAL TO RAISE MEDICAL EDUCATION AND PRODUCE ENOUGH DOCTORS,DENTIST AND NURSES TO IMPROVE OUR HEALTH EDUCATION AND SERVICE TO OUR FELLOW CITIZENS AND TO CREATE MOR CHECK AND BALANCES SOTHAT NO BODY CAN BE HERE FOR YEARS AND USE IT AS ONE'S BUSINESS HOUSE OR CORPORATE BODY.
DR.D.R.NAKIPURIA
AMBIKA CHIKITSHALYA
29 AGRASEN ROAD
SILIGURI-734005,09434143550


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Aug13
NDM1-BACTERIA IN INDIA -IS REALLY THREAT ?
Recently just published Article in a prestigious and reputed Jounal of World fame "LANCET" by an Indian scientist on presence of NDM-1 Bacteria,originating from New Delhi, Called New Delhi Metallo-beta-Lactamase-1,a new Superbug ,is really a new threat to World and our country too.But the way it has been published with an inference at last paragraph issuing a warning to all coutries and persons of World to be ware of going to India as if it is only hub and concentrated centre of this newly discovered Gram Negative Bactria or called BUG and adding name of our capital "NEW DELHI" to its name only on the basis of one patient who got treatment from New Delhi before detection of this Bacteria from his blood in Sudan,having no knowledge whether he was carrying it before treatment in India and then sporidacally adding that it is also found in Pakistan,Bangladesh and even in UK raise seroius question regarding authencity of such publication funded by two multi national Drug companies who make medicines ,Antibiotics for killing Bacterias and secondly by maligning India to prevent Foregners coming to INDIA for Treatment leaving UK and European and America .This bacteria like all bacteria might be prevalet in all parts of World but as no research has been done carefully to identify it in various part of World cannot be accepted as it is found mainly in New Delhi /India/Pakistan/Bangladesh only.
If Journal like Lancet is also manipulated like this then our whole Humanity is under threat ,any body can get any thing published to control or manipulate any thing to market or defame any product but once it is coming to world of Health it is a really serious question for humanity as corruption,manipulation favourism or criticism like such will spoil our Human Enviornment of turst and belief completely.
Therefore ,it is not only limited to Our Politicians,Health Ministry Parliament,ICMR,Medical Associations and Doctors of India but of whole World should protest against it in India and whole world ,serois objection should be stated at WHO level as why such reports were published in this manner to malign the name of a country to check "MEDICAL TOURISM" and such efforts should be nipped in the bud today and even in future sothat Commerce and Market should atleast spare Health System for giving wrong informations otherwise whole Humanity will collapse.
But it does not mean that we shall not take precautions,we should take extra effort in sterilisation of our Operation Theatre,Post up Wards and Preop Wards and post Op care somuch clean and clear that such Bacteria never infect any patient whether Indian or from outside under our treatment.
we know that Bactrias are known for mutations to save its progeny from devastation by bringing change in ts plamid and cell wall proteins. esearchers and is resistant to all known antibiotics. These are not being killed by modern Carbopenams(meropenam)and other Beta Lactamase Inhibitors(Tazobactum,sulbactum,pipercillin) as a result more infection to wounds will come to a normal patients in our hospital and those compromised like diabetics,suffering from cancer,HIV,getting,immunosupressants for transplants, immunological disorders,on steroid,cancer chemotherapy,elderly and childrens.

Lancet Infectious disease journal reports 50 such cases. Most of them have carried this infection from India, Pakistan and Bangladesh. The superbug NDM-1 is named after the national capital, where a Swedish patient was reportedly infected after undergoing a surgery in 2008. It is much more dangerous than the notorious MRSA infection.
MDM-1 is an enzyme produced by certain bacteria, which allows them to neutralize the harmful effects of carbapenem one of the most powerful types of antibiotics. Currently no new types of antibiotics are in the development pipeline that will be effective against it. Enzymes such MDM-1 are produced by strands of DNA which bacteria are known to transfer between one another. Currently E Coli and Klebsiella Pneumoniae are the two bacteria who are host to MDM-1. What makes the superbug more dangerous is its ability to jump across different bacterial species. The superbug has the potential to get copied and transferred between bacteria, allowing it to spread rapidly. If it spreads to an already hard-to-treat bacterial infection, it can turn more dangerous.The current treatment option is to treat them with a cocktail of antibiotics. Most new antibiotics currently under development are effective only against gram positive bacteria like super bug MRSA. Unfortunately, bacteria that carry the NDM-1 enzymes are gram negative.

A joint study was led by Chennai-based Karthikeyan Kumarasamy, pursuing his PhD at University of Madras and UK-based Timothy Walsh from department of immunity, infection and biochemistry, department of medicine, Cardiff University. They found the bug in most of the hospitals in Chennai and Haryana with estimated prevalence of this infection 1.5%. They reported the superbug in 44 patients in Chennai, 26 in Haryana, 37 in the UK and 73 in other places across India, Pakistan and Bangaladesh.gram negative sepsis with culture report: resistant to all antibiotics. We have been seeing such cases in the last few years. Now we have a name for this disease. Many of the doctors are deying its existance and linking it to a move against medical tourism in India. But the ICMR, NICD should work on it and come out with guidelines for this infection as no one can deny the fact that we do see cases of gram negative sepsis with E Coli or Klebsiella with culture report resistant to all antibiotics.

Carbapenemases are carbapenem-hydrolyzing beta-lactamases that confer carbapenem resistance.while Class B enzymes require the presence of zinc for activity (and hence are referred to as metallo-beta-lactamases).Class B beta-lactamases: are also known as the metallo-beta-lactamases (MBLs), which are named for their dependence upon zinc for efficient hydrolysis of beta-lactams. As a result, MBLs can be inhibited by EDTA (an ion chelator), although they cannot be inhibited by beta-lactamase inhibitors such as tazobactam, clavulanate, and sulbactam.
Acquired MBLs consist of genes encoded on integrons residing on large plasmids that are transferable between both species and genera.In a hospital outbreak involving 62 patients (including 40 intensive care unit patients), for example, an MBL gene (bla IMP-4) spread among seven different gram-negative genera (Serratia, Klebsiella, Pseudomonas, Escherichia, Acinetobacter, Citrobacter, and Enterobacter).Laboratory detection of MBL-producing organisms can be especially difficult if the organisms carry "hidden" MBL genes; The MBL E-test (a commercially available assay) cannot consistently identify MBL-producing organisms that are truly resistant to carbapenems. Therefore, MBL-producing organisms should be considered carbapenem-resistant regardless of carbapenem susceptibility results.

Other identification methods take advantage of the zinc dependence of MBLs by using EDTA, which chelates the zinc. Combination disc tests using imipenem and EDTA discs or using two carbapenem discs (including one with EDTA incorporated) have been reported. A more sensitive MBL detection method uses an agar plate with three components: a double disc synergy test with imipenem and EDTA discs, a combined disc test comprising two imipenem discs (with one disc also containing EDTA), and an aztreonam disc to detect aztreonam susceptibility. Carbapenem susceptible isolates that are resistant to both ceftazidime and ticarcillin-clavulanate should be considered for MBL testin Genotypic identification using PCR amplification with primers specific for MBL genes (eg, blaVIM or blaIMP) is an accurate method for the detection of MBL-producing organisms.(Source uptodate)

Therfore,we are not against its finding but its conclusion and attribution to one country India ,more and more reseaches and studies are needed to confirm its real presence in World and how it comes and persist and before doing enough studies such publication with infernces in reputed journals should be avoided otherwise whole Humanity will be at stake and Market and commerce will win over our Human Value.
Dr.d.R.nakipuria
Teacher In North Bengal Medical College for undergarduate and Post Graduate
Ambika Multispeciality Hospital
29 Agrasen roadSiliguri-734005


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Aug10
The Prime Cause and Prevention of Cancer with two prefaces on prevention.
Revised lecture at the meeting of the Nobel Laureates on June 30, 1966 at Lindau, Lake Constance, Germany

by Otto Warburg Director, Max Planck-Institute for Cell Physiology, Berlin- Dahlem

Dr. Otto Warburg, twice Nobel Laureate, awarded the Nobel Prize for Physiology or Medicine in 1931 for his research on cellular respiration, explains:

“The growth of cancer cells is initiated by a relative lack of oxygen. Cancer cannot live in an oxygen-rich environment…Cancer has only one prime cause. It is the replacement of normal oxygen respiration of the body’s cells by an anaerobic (i.e., oxygen deficient) cell respiration.”

Going into greater detail in The Prime Cause and Prevention of Cancer, he writes: “…the cause of cancer is no longer a mystery, we know it occurs whenever any cell is denied 60% of its oxygen requirements.

Cancer, above all other diseases, has countless secondary causes. But, even for cancer, there is only one prime cause. Summarized in a few words, the prime cause of cancer is the replacement of the respiration of oxygen in normal body cells by a fermentation of sugar. All normal body cells meet their energy needs by respiration of oxygen, whereas cancer cells meet their energy needs in great part by fermentation.

All normal body cells are thus obligate aerobes, whereas all cancer cells are partial anaerobes.” Compare Otto Warburg On The Prime Cause & Prevention of Cancer: Respiration of Oxygen in Normal Body Cells vs. Fermentation of Sugar in Cancer Cells.

Please download here the full Cancer Protocol of Otto Warburg (56 page pdf):
http://new-planet.net/pdf/O-Warburg-CancerProtocol.pdf


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Jul22
HAV & OTHER VIRAL INFECTIONS OF LIVER
HEPATITIS-A VIRUS (HAV)
INTRODUCTION:-
Known as Infectious Hepatitis. In 1973 this virus was detected in stool. In following years specific serologic assay & isolation of HAV in cell culture were done to study the epidemiology & prevention. Commonly transmitted by fecal-oral route via contaminated food or water. Incubation period is 2-6 weeks. In developing countries due to poor hygiene standard the incidence is high. Infection causes no clinical signs in >90% of children & offers lifelong immunity having special significance in indigenous population.It does not have a chronic stage & does not cause permanent liver damage. Vaccine is helpful in controlling out break.
VIROLOGY:-
Belongs to Picornaviridae family with genus Hepatovirus. HAV is icosahedral in shape without envelope, having diameter of 27- 28 nm. HAV survives exposure to ether, acid at pH 3, heat exposure at 60o C for 60 minutes but inactivated at 85 o C for 1 minute. HAV is capable of surviving sea water (4%), dried faeces at room temperature for 4 weeks(17%),in live oysters for 5 days(12%).Only one serotype of HAV is known & there is no antigenic cross-reactivity with B,C,D,E,F,& G. The HAV genome consists of positive sense RNA which is single stranded & linear. The HAVRNA has a long open reading frame consisting of 6681 nucleotides & covalently linked to a 5’ terminal protein& a 3’ terminal polyadenosine tract. HAV replication in cell culture takes weeks to months depending on metabolic activity of host cell. In the life cycle of the virus the 1st step is attachment to cell surface receptors, the location & function determine tissue tropism .Though exact mechanism of entry of HAV in to cell is not known probably through surrogate-receptor binding mechanism. A surface glycoprotein named HAVcr-1 has been identified as receptor for HAV. Experimental data suggest that HAVcr-1 not only serves as an attachment receptor but may facilitate un coating of HAV& its entry to hepatocytes. After entry of HAV the viral RNA is un coated , cell host ribosome bind to viral RNA forming polysomes & HAV is translated to large polyproteins which are organized to 3 regions:P1,P2,P3.The P1 encodes structural proteins VP1,VP2,VP3 &VP4.P2 & P3 encode non structural proteins associated with viral replication.
Numerous strains of HAV exists with variability of nucleotide sequences Human HAV strain have 4 genotypes (I,II,III,VII) where as simian have IV,V,VI genomes. But despite heterogeneity of nucleotide sequence the antigenic structure is maintained. HAV VP1/2 & 2C are thought to be responsible for virulence. Among many strains of HAV HM175 &CR326 are important as they are used for production of vaccine. Variation of HAV genome are responsible for fulminant hepatic failure (FHF) during acute HAV infection.
HAV can be inactivated by Chlorine treatment, formalin(0.35% 37C,72 hours),peracetic acid(2%,4 hours)beta-propiolactone(0.25%,1 hour), UV radiation(2µw/cm2/min)
EPIDEMIOLOGY:-
In US the annual calculated rate is 93,000.The highest rate is among children between 5-14 years. But it can occur in any age. The epidemiological risk factors in US-unknown (57%), sexual or household contact (12%),
International travel(9%),male homosexual(8%),injection drug users(5%),child or employee in day care(1%),food & water borne(1%),other contacts(7%).
HAV infection usually follows one of the three epidemiologic patterns:-
1. In poor sanitary conditioned countries most children at an early age are infected showing 100% Anti-HAV antibody in their serum indicating sub clinical infection. Symptomatic infections has risen to 5 years & older groups. Differs in income groups. About 95% children of low income families are infected.
2. Second pattern is seen in industrialized countries where prevalence of Anti-HAV in children is 10% & adults 37%.
3. Third pattern is seen in closed or semi closed communities like South pacific. HAV infects entire population, which then become immune. Only new borne become susceptible.
TRANSMISSION:-
The primary route of transmission is fecal-oral route by either person to person contact or ingestion of contaminated food or water.
Rare routes:- Parenteral after blood transfusion, Injection users & non injection illicit drug users
Homosexual males
Detection of HAV & infectivity of secretions & excretions
Stool:- HAV detected during incubation & for several weeks after onset. HAV is found in 45% & 11% during 1st & 2nd weeks respectively. HAV-RNA (by PCR) is detectable up to 4-5 months.
Blood:- Viraemia present during incubation. Blood collected 3-11 days prior to onset causes post transfusion, Infection.
Bile:- Detected in Chimpanzees.
Urine:- Detected in viraemia phase. Urine contaminated with blood is infectious.
Nasopharyngeal secretion:- Unknown to human.
Semen, vaginal fluid:-Uncertain. HAV detected in viraemia phase.
Virus spread is common in poor sanitation & over crowding. Common source (e.g. water, restaurant) outbreaks are typical.
PATHOGENESIS:-
HAV once ingested survives gastric acid, pass to mucosa of small intestine & reaches liver via portal vein. Entering into hepatocytes by uncertain mechanism replicate in the cytoplasm (seen by E/M as fine granules) but not in the nucleus. HAV is distributed through out the liver. Though antigen is detected in lymphnodes, spleen, kidney they exclusivey replicate in hepatocytes. Once the virus is mature it reaches the systemic circulation via hepatic sinusoids & released to billiary tree through bile cannaliculi, pass into intestine & faeces. The hepatocyte injury is not clear as HAV is not cytopathic. Immunologically mediated cell damage is more likely. The anti HAV could result in hepatic necrosis duringmmunologically mediated elimination of HAV.
CLINICAL FEATURES:-
Incubation period is 2-4 weeks, rarely up to 6 weeks.
Course is usually acute self limiting, prolonged or relapsing, cholestatic phase but chronic infection does not occur. Mortality is low in healthy persons & morbidity is high in adults & older children.
More in men in all age groups.
HAV infection usually presents in 5 different clinical presentations:-
1.-Asymptomatic without jaundice
2.-Symptomatic with jaundice & self limited-8 weeks
3.-Cholestatic with jaundice lasting 10 weeks or more
4.-Relapsing with 2 or more bouts of acute infection over 6-10 weeks
5.-FHF
Children below 2 years are usually asymptomatic jaundice in 20%. Children over 5 years or more are symptomatic (80%).Symptoms are more in adolescent or adults. Cholestatic type is a rare variant where jaundice persists for long period & subjected to invasive diagnostic procedures. Relapsing course is observed in 10% cases where shedding of HAV in stool is detected. This variant is benign & resolve ultimately. Neither cholestatic nor relapsing variant has greater mortality & treatment is symptomatic. Unlike Hepatitis-E, HAV has no higher mortality in pregnant women.
Usual prodromal symptoms are fatigue, weakness, anorexia, nausea, vomiting, abdominal pain. Less common symptoms are fever, headache, arthralgia, myalgia, diarrhea. Dark urine precedes symptoms (90%).Symptoms may last for few days to 2 weeks & decrease after onset of jaundice. Right hypochondriac pain & mild tender hepatomegaly (85%), splenomegaly (15%), cervical lymphadenopathy (15%) may be noted.
Complete clinical recovery in 2 months (60%) & in 6 months (100%).
Overall prognosis is good in healthy adults.
Fulminant hepatic failure (FHF):-
FHF is rare in children, adolescent or young adults.
Case fatality in aged >49 years is 1.8%.
Usually manifest in 1st week of illness (55%) & first 4 weeks (90%).Rare after 4 weeks.
It is higher in hyperendemic area like India.
The increased among elderly, associated CLD.
Extra hepatic manifestations:-
Less frequent than HBV. Consists of evanescent rash(14%), arthralgia(11%), leukocytoclastic vasculitis, glomerulonephritis, arthritis which are due to immune complex mechanism.Cutaneous vasculitis are seen in legs & buttocks.Skin biopsy reveal presence of IgM anti HAV & complement in vessel wall. Vasculitis & arthritis are associated with cryoglobulinemia where cryoglobulin contains IgM antiHAV. Other extrahepatic manifestations include toxic epidermal necrolysis, fatal myocarditis, renalfailure,optic neuritis, transverse myelitis,polyneuritis, cholecystitis, thrombocytopenia, aplastic amaemia, red cell aplasia.
Auto immune hepatitis (AIH) after HAV: - HAV rarely trigger the onset of Type-1 AIH.
DIAGNOSIS:-
Acute HAV is to be differentiated from other causes of viral hepatitis, AIH & other causes of hepatitis by serological tests. Many times it may be difficult due to associated chronic HBV or HCV infection.
In acute HAV IgM-antiHAV antibody is positive from the onset of symptoms & usually remains +ve up to 4 months.In some low levels may be detected up to 1 year.IgG antiHAV antibody is detected at the onset & remain +ve through out life indicating a marker of previous infection.
HAV-RNA (by PCR) has been detected in stool, blood &liver. HAV-RNA is usually undetectable in FHF than non-fulminant hepatitis. It is suggested that detection of IgM antiHAV coupled with nondetectable or low titer of HAV-RNA may signal ominous prognosis & require liver transplant.
During acute phase the liver enzyme ALT is high.
TREATMENT &PREVENTION:-
High risk populations are targeted for vaccination. Childhood vaccination have a +ve effect in reducing incidence.
High risk groups:--
Healthy persons traveling to endemic area, occupation likelihood of exposure, family members of
Infected person, adopt infant or child from endemic area.
Persons with CLD.
Persons who are HIV +ve.
Homosexual man.
Users of injection & illicit drugs.
Clotting factor disorders.
Persons living in high or intermediate rate of HAV infection.
No specific treatment. Symptomatic treatment is the rule. Advise rest, avoid fatty food & alcohol, take balanced diet & proper hydration.
Attention of proper sanitation.
Role of Immune Globulin (IG):-Use of pre exposure prophylaxis is unnecessary due to availability of vaccine. In post exposure prophylaxis IG should be given within 2 weeks of exposure in a dose of 0.02 ml/kg IM.IG can cause fever, myalgia. IG can safely be given along with vaccine.
HAV vaccine: - Two inactivated HAV vaccine are available ,to be given IM in deltoid area.
HAVRIX & VAQTA are 2 vaccines derived from HAV grown in cell culture. They are purified, formalin inactivated & contains Alum as adjuvant. HAVRIX is prepared from HM175 strain & VAQTA from CR326 strain of HAV virus, Both are safe & immunogenic. Immunity lasts for 20 years or longer.
Common side effects are soreness at injection site (56%), headache (14%),malaise(7%). Some unexplained adverse reactions are neurologic, haematologic, &autoimmune syndrome.
A combination formula of HAV &HBV is available with excellent safety &efficacy (TWINRIX).
Dosing schedule-----
HAVRIX - 2-18 years 0.5ml 0,6-12 months.
>18 years 1 ml 0, 6-12 months.
VAQTA- 2-18 years 0.5 ml 0, 6-18 months.
>18 years 1 ml 0, 6-18 months.
TWINRIX- ≥ 18 years 1 ml 0, 1, 6 months.
PROGNOSIS:
Death usually occurs if patient is already suffering from other hepatitis like B,C & AIDS. Young children experience mild form whereas adults much severe form.

HEPATITIS-D VIRUS (HDV)

INTRODUCTION:
Hepatitis D(delta) virus was discovered by Rizzetto in 1977 as an unique nuclear antigen in hepatocytes of patients infected with HBV, when he observed a new antigen other than surface, core, & e antigen.
EPIDEMIOLOGY:
Distributed worldwide.5% of HBV carriers are infected with HDV with a burden of 15-20 millions. Highest prevalence in South America & Mediterranean basin. The incidence of HDV is declining in some countries due to screening of blood donors for HBsAg. However HDV remains among injection drug users. Among 3 genotypes of HDV(I,II,III) genotype-I is prevalent in Mediterranean countries, Africa, Europe, North –America. Different subtypes within this genotypes are seen in Africa. Genotype-II is seen in Japan &Taiwan with mild liver disease. Genotype -III is seen in South America associated with high mortality & a lesion in liver cell is called morula cells. Various genotypes of HDV & HBV may interact though their effect on HDV is not clear. But infection with HDV genotype III&HBV genotype F cause severe hepatitis. The mode of transmission of HDV is closely linked to HBV mainly parenteral route. Sexual transmission & familial clustering seen in endemic areas. In Asian population it is primarily in injection drug users. It is not clear why HDV is so frequent & lethal in Amazon basin, nonexistent in Asia & fairly benign in Greece & South pacific. Researchers suspect different HDV genotypes cause varying degrees of liver damage.
VIROLOGY:
The 1.7 kb single strand negative sense HDV-RNA genome shares many features with plant viroids.Unlike plant viroids HDVRNA encodes a protein hepatitis delta antigen (HDAg). The virion consists of HDV genome complexed with 70 copies of HDVAg in an envelope protein composed of lipid & HBsAg .The protein envelope contributed by HBV protects HDV-RNA-HDAg complex. Once HDV with its HBV envelope protein enters the host the HDV-RNA-HDAg complex migrates to the nucleus. Viral replication proceeds in the nucleus.
During translation two forms of HDAg are formed, short form (HDAg-S),long form(HDAg-L) the later having 19-20 more amino acids. The long & short forms have opposite effects on viral replication, the short form as facilitator, the long form as inhibitor. In states of high replication HDAg-S is produced.
HDV is classified as a single separate genus of Deltaviridae family. The consensus is that HDV is a satellite virus, which is a sub viral particle carrying distinct nucleic acid, usually RNA, requires helper virus for transmission & multiplication, differ in nucleic acid of helper virus. No other animal virus ha been identified as satellite virus. It is the smallest virus, unique virus & most virulent. The genetic information is stored in RNA where as in others it is stored in DNA.
TRANSMISSION:
Through blood & blood products like HBV. Unlike HBV sexual transmission is less though it can be transmitted by barrier free sexual activity. Homosexuals are prone but less than injection drug users. Vertical transmission is rare.
PATHOGENESIS:
Mechanism is not clear. HDV is not directly cytotoxic. Combined infection of HBV &HDV may have a direct cytotoxic effect or an enhanced immune response against two viruses. HDV may be related to immunological response s evidenced by presence of antibodies to liver-kidney microsome (anti-LKM), thymocytes, nuclear lamin C. The ability of HDV to cause hepatic necrosis is by expression of HBV. Blood is potentially infectious in all phases of acute & chronic infection, but most infectious prior to onset of illness & symptoms.
NATURAL HISTORY:
The incubation period varies from 21-90 days. Depending on HBV two types of HDV occurs.
1. Coprimary infection-Simultaneous infection of HDV &HBV.
2. Superinfection-HDV is superimposed on chronic HBV.
HDV infection has a varying influence on the course of HBV. The severity of HDV infection may vary with frequency of HDV in a population, with level of HBV viremia, with interaction of specific HBV &HDV genotypes.
Co primary infection:-Most often in injection drug users. As both resolve in most cases chronicity is <5%. Some data suggest enhanced risk of fulminant hepatitis & death.
Super infection:-Can lead to severe hepatitis & acute decompensation. There occur high levels of HDV viremia. As HDV replication inhibits HBV replication there occurs decline of HBV-RNA. Rarely disappearance of HBsAg & appearance of antiHBs occurs. Chronic HDV infection frequently occurs than confection (70%), characterized by persistent of HDV viremia & detectable HDV-RNA in serum. The persistent replication of HBV &HDV lead to progressive hepatitis & cirrhosis within years. More rapid course lead to end stage liver disease.
The clinical course of a triple infection HBV,HDV&HCV is dominated by HCV.The patients often have severe episode of acute hepatitis. The chronic stage slowly progress like HDV or HBV.
CLINICAL PRESENTATION:
Co infection typically manifest as self limiting acute hepatitis. Some show double peak of serum aminotransferase due to delay in HDV replication after HBV replication. Detectable serum IgM antiHBc, IgM antiHDV, HDV-RNA, HBV-DNA, HBsAg are seen. The enzymes return to normal after infection resolves.
HDV super infection manifest as acute hepatitis in a stable HBV carrier, mimicking spontaneous flare up of HBV infection. But presence of HDV-RNA and IgM anti HDV is the marker for super infection. As IgM anti HDV is seen in both co infection and super infection serologic finding of IgM anti HBc indicates co infection of HBV.
In association of HBV complicate acute liver failure, develop liver cancer and chronic infection. Combined mortality is 20%.Symptoms are similar to other viral infection, like fever, jaundice anorexia, malaise, dark urine, rash, nausea,arthralgia. But patients are more ill than HBV alone. Cirrhosis develops in 60-70% (higher than B or C ).
DIGNOSIS:
The useful markers are HDAg, antibody to HDAg(Anti HDV) , HDV RNA, and immunohistochemical starting of HDAg in liver.
• Detection of HDV-RNA by reverse transcriptase PCR(RT-PCR) is most reliable with 100% sensitively and earliest marker seen during the course without any other markers and high level is associated in severe cases. It also indicates efficacy of treatment and viral eradication. HDV RNA can be detected in liver by hybridization technique which is less sensitive than RT-PCR.
• HDAg is demonstrated in Liver cells by immunohistochemical staining but reliability decreases as disease become chronic. Presence of neutralizing antibody also interfere its detection.
• Detection of AntiHDV does not confer protection against HDV. Either IgM or IgG AntiHDV is detected. IgM appears in serum early and IgG later. IgM persists into chronic HDV infection and a marker of serious infection. As the disease turn to chronic the IgM changes from monomeric(S) form to multimeric (19S). IgG persists for a long time in immunocompetent person indicating chronic or previous infection.
TREATMENT:
Treatment of HDV is disappointing. Interferon is the only promising drug. Nucleoside analogs are not effective for HDV. Several clinical trials evaluated the efficacy of interferon in treating chronic HDV. Pegylated interferon treatment has not been reported. Nucleoside analogs like Lamivudine have not shown influence on HDV replication and not recommended. Co infections with HIV or HCV have poor rates of response. Usually Interferon alfa 9 million unites 3 times weekly for 1 year is recommended. Treatment for longer duration may be beneficial but to be considered on the basis of histologic severity, HDV-RNA response, and patient tolerability. Use of Pegylated interferon needs further study.
Advanced molecular biology may help to identify specific inhibitor of HDV replication. Prenylation (addition of prenyl lipid like farnesyl) of HDAg-L is a critical determinant of HDV particle assembly. In vitro it is shown that prenylation can abolish particle production.
PREVENTION:
Vaccination against HBV confers protection against HDV. Groups showing high rate of HDV infection should be vaccinated. Once HBV are eliminated HDV can not replicate without HBs antigen and also disappear. No vaccine is available against HDV. Super infection can be reduced by safer sex practice, avoiding blood or blood product contact and not sharing needles.

HEPATITIS-E VIRUS(HEV)
INTRDUCTION:
Hepatitis-E is a form of acute, icteric, self limited viral hepatitis caused by HEV. It was recognized in 1980 during epidemics at Delhi, Kashmir. Subsequently the virus and genomic sequence were identified. In retrospect study similar enterically transmitted hepatitis occurred in Europe in 18th and 19th centuries.
VIROLOGY:
It is a small RNA virus , 32-34 nm in diameter, unenveloped and icosahedral shape. HEV-RNA is 7.2 kilo bases in length, single and positive stranded 5-’capped and polyadenylated. It contains 3 open reading frames (ORSs). ORF1 encodes nonstructural protein, ORF2 encodes the viral capsid protein and ORF3 encodes a protein of unknown function. HEV attachment and entry to hepatocytes, its replication and release mechanism in unknown. The virus is classified to genus Hepatitis-E like virus and phylogenetically related to Togavirus. Geographically various isolates of HEV are isolated like genotype1 (Asian Strain), type-2(Mexico Strain). All genotypes share at least one major serologically cross-reactive epitope. Swine HEV is genetically different from Human HEV in India but similar in other parts.
EPIDERMILOGY:
Several epidemics have been found in different parts of the world. Overall attack rate is 1-15%, higher in adults (3-30%) than children (0.2-10%). The male female ratio varies from 1:1 to 4:1. High attack and mortality rate occur in Pregnant women. The nature of epidemics range from single peaked, short lived outbreaks to prolonged, multipeaked lasting for more than 1 year.
Classification of HEV genotypes:-
Genotype Geographical Origin
1 Asia
1A India, Myanmar, Nepal
1B China, Pakistan, Soviet Union
1C Africa
1D India
2 Mexico, Africa
3 U.S
4 China, Taiwan
5 Italy
6 ,7 Greece
8 Argentina
Prevalence rates of antiHEV, which is detectable in all geographical areas are higher among endemic (10-40%) than nonendemic (1-5%).
Reservoir:-Domestic animals like pigs have been reported. A number of rodents has also been identified. The disease is thought to be a zoonosis as animals like pigs & deer are the sourse.
TRANSMISSION:
Predominantly through fecal-oral route. Outbreaks usually occur following heavy rain or flood & in Summer due to increased contamination. Person to person contact is uncommon & secondary attack among household contact is 0.7-2.2%. Maintenance of continuous virus in endemic area are due to sub clinical HEV infection, animal reservoir harboring HEV- like viral agents & prolonged fecal shedding of virus. Sporadic hepatitis which is demographically & clinically similar to epidemic form accounts for 50-70% of acute cases in endemic areas. Some are related to travel to endemic areas. Occasionally it can be due to undercooked meat. One study shows HEV transmission through blood but data is inadequate. No evidence of parenteral or sexual transmission.
PATHOGENESIS:
Entering through oral route virus reaches liver through unknown mechanism. HEV can be detected in stool 1 week before the onset of illness & up to 2 weeks there after. HEVRNA is detected in serum for 2 weeks after the onset of illness in all patients. HEV antigen (HEVAg)is expressed in hepatocytes as early as 7 days after infection in >50% of cells. But the number decreases sharply when serum ALT is increased. The onset of elevation of ALT & histopathologic changes in liver correspond to the appearance of antiHEV (IgG,IgM) in serum. This suggests the liver injury may be due to immune mediated specially lymphocytes infiltrating liver have a cytotoxic/suppression immunophenotypes. Like other forms of hepatitis there occurs ballooned hepatocytes, acidophilic bodies, focal parenchymal necrosis, inflammatory infiltrates in the lobules, enlarged portal tracts. About 50% have cholestatic hepatitis characterized by canalicular bile stasis & gland like transformation of parenchymal cells with less marked hepatic degeneration & necrosis. In severe cases sub massive or massive necrosis & collapse of parenchyma are seen.
CLINICAL FEATURES:
The incubation period is 2—10 weeks.There are varying clinical presentations.
1.Acute icteric hepatitis:-Onset is insidious. Prodromal phase(1-4days) have flulike symptoms, fever, mild chill, abdominal pain, anorexia, nausea, vomiting aversion to smoking, clay coloured stool, dark urine, diarrhea, arthralgia, asthenia & transient macular rash.Prodromal symptoms disappears with onset of jaundice except dark urine, clay stool, & itching. On examination there is jaundice, soft tender mild hepatomegaly & splenomegaly. Laboratory tests show bilirubinuria, conjugated hyperbilirubinemia, marked elevation of aminotransferase &gamma glutamyl transpeptidase. Elevation of ALT may precede the onset & level does not correlate the degree of hepatic injury. Mild leucopenia with lymphocytosis occurs. Serum ALT & bilirubin normalize by 6 weeks. Ultrasonography shows mild hepatomegaly with increased parenchymal echogenicity, gall bladder edema, prominent portal venules &mild splenomegaly. Acute infection usually self limited. The case fatality is 0.5-4%. Chronic hepatitis or cirrhosis do not occur.
2. Cholestatic hepatitis:-In some cases there is persistent jaundice (2-6 months), itching, marked elevation of enzymes. Ultimately spontaneous resolution occurs.
3. Anicteric hepatitis:-Some have nonspecific viral like symptoms with raised enzymes without jaundice.
4. Asymptomatic & anicteric:-Occurs frequently in younger age groups.
5. Fulminant hepatic failure:-In small cases sub acute or fulminant hepatic failure occurs mostly in endemic areas.
Pregnant women particularly 2nd & 3rd trimester are frequently affected. Fulminant hepatic failure, abortion, stillbirth, neonatal deaths are increased. The cause of high incidence is unknown.
DIAGNOSIS:
1. Detection of HEV-RNA-Detected in stool & serum using PCR.
2. ELISA to detect immunoglobulin’s (IgM,IgG)-Presence of IgM antiHEV where as IgG antiHEV indicate convalescent phase or past infection. IgM appears early, lasting for 4-5 months, detected in 80-100% of cases during outbreaks. IgG appears few days after IgM and titer increases in convalescent phase & remain for 1-5 years.
TREATMENT & PREVENTION:
Acute infection is usually self limited requiring supportive treatment. In fulminant cases requires measures to decrease cerebral edema or liver transplant. In pregnancy no proved benefit of terminating pregnancy is seen. Hemorrhage due to deranged coagulation can be treated with fresh frozen plasma.
PREVENTION-In endemic areas depends on supplying clean water& strict sewage disposal. Boiling of water may reduce risk. Isolation is not indicated.
Role of immunoglobulin given in pre or post exposure is not proved. Occurrence of epidemics in endemic areas indicate that anti HEV is not fully protective or the antibody declines with time to non protective level.
Various trials of vaccine are in the process. An experimental HEVDNA vaccine tried in primates. Prospect of vaccine even having short term protection is needed for travelers & pregnant women.
HEPATITIS F VIRUS
It is a hypothetical virus linked to hepatitis. Several cases emerged in 1990 but reports not substantiated. In 1994 viral particles detected in stool of post transfusion nonA-nonE hepatitis and injection of these materials to Indian rhesus monkey caused hepatitis & named as hepatitis F or Toga virus. Further investigation failed to confirm the existence and it was delisted.
HEPATITIS G &GB AGENT INFECTION

INTRODUCTION:
Hepatitis G virus (HGV)& GB agents(GBV) are isolates of same virus. GBV has been identified as 3 different types e.g. GBV type A(GBV-A), GBV type B(GBV-B), GBV type C(GBV-C).About 96% homology of genome occurs between HGV&GBV-C indicating two strains of same virus. The term hepatitis G virus is questioned due to lack of association between GBV-C/HGV & acute or chronic hepatitis. For clarity GBV-C/HGV is referred as GBV-C.
VIROLOGY:
GBV-C is a positive strand RNA virus genome containing 9400 nucleotides encoding about 2900 amino acids, classified as a member of Flaviviridae family. GBV-C shares 44% &28% homology with GBV-A &GBV-B respectively. Though GBV-C is similar to HCV it is clearly distinct. One long open reading frame encodes a single large polyprotein with structural protein encoded at 5’ amino terminus & nonstructural protein encoded at 3’ carboxyl terminus. The structural proteins differ in GBV-C &HCV. Though there are 2 glycoproteins E1&E2 of GBV-C the difference of polymorphism inE2 accounts for less chronic viremia in GBV-C infection (25%) than HCV(50-70%). In contrast the nonstructural proteins of HCV &GBV-C are similar. HCV &GBV-C differ in tissue tropism. In contrast toHCV, GBV-C does not show hepatotropism. But like HCV it shows lymphotropic property as negative strand RNA are found in mononuclear cells, bone marrow & spleen. Due to its interaction inside lymphocytes there is some interaction between HIV &GBV-C.
EPIDEMIOLOGY & TRANSMISSION:
GBV-C is found world wide(2-5%). At least 5 genotypes identified according to geographical distribution.Genotype1 (West Africa), genotype2 (Europe, US), genotype3 (Asia), genotype4 (Southeast Asia), genotype5 (South Africa).
The development of antibodies to GBV-CE2 correlates with loss of viremia & suggest past exposure and clearance of GBV-C infection. Current & past infection is found among parenteral risk factors & voluntary blood donors. Frequent blood exposed patients are viremic and seropositive toE2 antibodies (50-70%). Past or current GBV-C infection may show normal ALT, posing a risk for transfusion transmission (raised ALT-exclusion criteria for donors). It can be transmitted sexually & vertically more frequently than HCV. Infected babies have no evidence of hepatitis or other sequlae. As
HCV& GBV-C are transmitted parentrally co infection is common. GBV-C viremia is seen in 20% of HCV infected persons where the rest 80% are seropositive toE2 antibodies. This suggests the high rate of natural clearance of GBV-C (75%) than HCV (25%). The virus can not be contacted through saliva, semen or any other body fluids other than blood.
CLINICAL FEATURES:
Though GBV-C is detected in many patients with non A to E acute or chronic hepatitis & may persists for years it does not cause liver (or any other) disease, even in immunocompromised patients. It does not modulate the course, response to therapy in HCV, HBV patients. It does not interfere liver transplant though the rate of viremia is more due to frequent transfusion. The duration of infection depends on age & immune status of the host. Childhood acquisition leads to chronic infection. In immunocompetent adults rapid viral clearance occurs. Chronic GBV-C hepatitis occurs in HIV patients. In contrast to HCV the development of antibodies toGBV-CE2 protects against reinfection. There is no clear association between GBV-C infection & HCC, nonHodgkins lymphoma, aplastic anemia, porphyria cutanea tarda or lichen planus.


DIAGNOSIS:
As it rarely causes human disease the diagnostic tests are reserved for research only. GBV-VRNA is detected by PCR. A test for antibody detection is also available.
GBV-C & HIV-It was observed that in HIV infected patients slow progression to AIDS & death correlated to GBV-C viremia. Co infected patients have better prognosis than HIV mono infected cases. In addition better antiretroviral therapy, rapid rise of CD4 count observed. The explanation of better response though not exactly known may be this virus prevents HIV from replicating frequently, thus extending the life span by inhibiting damage to the immune system.
TREATMENT:
As not associated with clinical disease, no treatment required. Those who are co infected with HCV treatment with interferon and ribavirin cause disappearance of GBV-CRNA from serum but reappeared in all cases after therapy completed.
TTV INFECTION

INTRODUCTION:-Identified in 1977 from a patient (initial-TT) in Japan who had acute post transfusion non A to G hepatitis.
VIROLOGY: TTV is a non enveloped, single stranded, negative polarity, circular DNA virus related to family of animal virus Circoviridae. The TTV genome is 3695 nucleotide long & contains at least 3 ORFs. Three messenger RNA (mRNA) are expressed by TTV. The protein product of largest mRNA (3kb long) functions as capsid protein. At least 16 genotypes have been identified with greater than 30% sequence divergence. TTV is believed to be hepatotropic as high viral level is seen in liver than serum. It also replicates in PBMCs and bone marrow cells.
EPIDEMIOLOGY & TRANSMISSION:-Found world wide & very common. Prevalence among blood donors are high.
Transmitted by all parenteral routes & high among hemophiliacs, IV drug users, haemodialysis & organ transplants. Also transmitted enterically (fecal-oral).
CLINICAL FEATURES:-In the first reported case there was acute hepatitis, viremia was detected 6 weeks after exposure &2 weeks before the rise of serum ALT.DNA was documented by PCR and ALT subsequently returned to normal. Viremia may persist for years in both immunocompetent & immunosuppressed persons. Most cases don’t have biochemical or histologic evidence of liver disease. It does not alter the natural history or response to treatment of HCV or HBVcases.
TREATMENT:--Protocol not studied. In a co infected HCV case treatment with PegIFN 6 of 10 cases cleared TTV viremia by end of therapy but majority relapsed within 6 months.

SANBAN, YONBAN, SEN &TTV LIKEMINI VIRUS (TLMV)
After discovery of TTV in 1997 similar viruses with small DNA genomes isolated in Japan. Sanban, Yonban and TLMV have been divided into 29 genotypes with diverge sequences. They are transmitted by parenteral & fecal oral route. None has been clearly associated with human liver disease so far.
In 1999 another virus identified in a HIV patient (initial SEN) which is a small, non enveloped, single stranded DNA virus, transmitted by parenteral &fecal oral routes. Vertical transmission may occur. No chronic infection occurs. Prevalence is high with parenteral risk factors particularly HCV co infection. Clinical significance of SEN virus is not clear. Fulminant course or CLD do not occur.
Most studies show no association between these viruses & human disease, nor any effect on course and response to treatment of chronic viral hepatitis.


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Jul22
OPPORTUNISTIC INFECTION IN HIV/AIDS
INTRODUCTION:
Opportunistic infections (OI) are the hall mark of immunodeficiency associated with HIV. They include opportunistic protozoan, fungal , bacterial , viral and other infections along with repeated episode of HIV infection. It is important to diagnose OIs, because acute infections are at times life threatening, effective prophylaxis result in better survival. The clinical manifestations are different than normal host. Various studies established the relationship between rising viral load and decreasing CD4+ count and progression of HIV. Timely chemoprophylaxis reduce the risk of OIs and effective ART therapy (anti retroviral) decreases viral load, restore immune function, reduce risk of OIs.

Certain patients in the developed and developing world do not have access to care or response to ART due to multiple reasons leading OIS as important cause of morbidity and mortality in HIV-1 infections. The therapy for OIs has changed substantially leading to new strategies for management.

CLASSIFICATION
AIDS (CDC classification category C diseases) is defined by the development of specified opportunistic infections or tumours. There is a correlation between CD4 count and HIV related infections.
TABLE – 1(CD4 COUNT AND ASSOCIATED INFECTIONS)
> 500 cells/mm3 Acute primary infection, Recurrent vaginal candidiasis
<500 cells /mm3 Pulmonary Tuberculosis, Pneumococcal pneumonia, Herpes Zoster, Oropharyngeal candidiasis, Extraintestinal salmonellosis, Lymphoid interstitial pneumonitis
<200 cells/mm3 Penumocystis carinii (jirovecii)pneumonia, Mucocutaneous herpes simplex, Cryptosporidium, Microsporidium, Oesophageal candidiasis, Miliary/extrapulmonary tuberculosis
<100 cells/mm3 Cerebral toxoplasmosis, Cryptococcal meningitis
<50 cells/mm3 CMV retinitis, CMV gastrointestinal diseases, Disseminated mycobacterium avium intracellulare
The Ols can be descried as per the system involved.
1. Pulmonary diseases seen in HIV (OIs)
• Bacterial: Streptococcus penumoniae, H. influenzae, Pseudomonas aeruginosa, Klebsiella penumoniae, Rhodococcus equi, Mycobacterium tuberculisis, Atypical mycobacteria
• Fungal: Penumocystis carinii (Jirovecii), Cryptococcus neoformans, H. Capsulatum, Coccidiodes emitis, Penicillium marneffi, Aspergillosis
• Viral - CMV, EBV, HSV, VZV
• Protozoal – Toxoplasma gondii, Strongyloides stercoralis
2. CNS
• C. Neoformans
• Toxoplasma Gondii
• JC Virus causing PML
• Others : Syphillis, M. tuberculosis, T. cruzi, HTLV – I infection, Acanthamoeba
3. G.I.T
• Fungus – Candidiasis, Histoplasma, Coccidioidomycosis, Penicillisis
• Bacterial – Salmonellosis, Shigella, Campyolobacter jejuni
• Virus EBV – (Oral Hairy leucoplakia)
CMV Colitis, Rotavirus, Adenovirus , HSV
• Protozoal infection : Cryptosporidiasis, Cyclospora, Micosporidiasis, E. histolytica, Isosporiasis, G. lamblia, C. difficile
4. Hepatobiliary – HBV and HCV infection
Fungus – C.immitis, Histoplasma
5. Genitourinary – Syphilis, candidiasis
6. Dermatological Condition
• Seborrheric dermatitis, Herpes simplex / Varicella zoster virus (VZV), Bacillary angiomatosis, Molluscum Contagiosum, Anogenital HPV (Human papilloma virus), Scabies, Syphilis, Fungal folliculitis rash (Fungal – Malassezia furfur), Dermatoplytic infections involving skin, nail
7. Cardiovascular
Cardiomyopathy – Cryptococcosus, Chagas disease, Toxoplasmosis
Pericardial Effusion - Tubercular
8. Rheumatological
Septic arthritis may be due to fungus C. neoformans, H. capsulatum, Sprorothrix schenckii, Systemic mycobacteria – M. haemophillum
9. Endocrine System
Adrenal gland involved in CMV, mycobacterial, cryptococcal, histoplasmosis
Thyroid – involved in P. carinii, CMV, toxoplasma, mycobacterial, cryptococcal
10. Haemopoetic System
Bone marrow suppressed by – Fungal, Mycobacterial and B19 parvovirus
11. Ophthalmic Disease
CMV Retinitis
HSV & VZV
P. Cariniii – Choroiditis
Toxoplasma - Chorioretinitis

Few common Ols are described in the paragraph following.


P.C.P. (Pneumocystis carnii pneumonia):
Very common infection and called as “ AIDS pneumonia”, occurring in 57% of children below 1 year and leading cause of interstitial plasma cell penumonia. It is a protozoan but closely related to fungi. The reservoir and mechanism of transmission is obscure but transmittd by direct air borne. The organism establishes in alveoli where it proliferates as an exracellular parasite producing interstitial oedema, hyaline membranes resulting in progressive hypoxemia and respiratory failure. The symptom tetrads are fever, cough, dyspnoea and tachypnea. Physical examination shows tachycardia, respiratory distress with accelerating tachypnoea and diffuse retraction without any specific auscultatory findings. Extrapulmonary penumocystitis involves L. node, spleen, liver, Thyroid, adrenal gland, kidney. Ophthalmic lesion of choroids, necrotising vasculitis resembling Burger’s disease, bone marrow hypoplasia, intestinal obstruction, heart. Associated with cystic lesion or calcification on CT or Ultrasound. Otic involvement cause polypoid in auditory canal.

Arterial blood gas analysis (ABG) shows progressive hypoxemia, respiratory failure. Chest X-ray shows signs of hyperinflation with peribronchial thickening , bilateral alveolar, interstitial in filtration, which spread outwards from hila. Further progression leads to bilateral airspace disease with air bronchogram, cavities, pleural effusion and spontaneous penumothorax, the last being characteristic.

The diagnosis is confirmed by Wright – Giemsa staining of induced sputum or Broncho-Alveolar Lavage (BAL). Trophozoites and intracystic trophozoites are seen. Prognosis is related to hypoxaemia (Alveolar – arterial O2 gradient - < 35 mm of Hg – Mild, 35-45 mm of Hg moderate and > 45 mm of Hg severe).

Treatment: The treatment is a medical emergency. The treatment of choice is Trimethoprim sulphamethoxazole (TMP-SMX) or Pentamidine. The other alterantive drugs used in adults are Dapsone – TMP, Clindamycin, Primaquine, Atovaquine.
TABLE – 2
Drug Schedule Remark
TMP-SMX 20mg of TMP/Kg/Day in 4 divided doses I/V for 21 days Restore to oral when patient responds
Pentamidine 4mg/Kg/Day,
Single Dose, I/V for 21 Days Reserved who cant tolerate TMP- SMX or no response after 7 days of therapy.
Dapsone – TMP
Clindamycin
Primaquine
Atovaquine
Mortality – 5-40% in treated and 100% in untreated cases.

PREVENTION:
Indication: All HIV infected children from 4 weeks to 12 months of life, in determinate status children from 4 weeks till HIV is excluded (4 months), HIV infected children above 1 year having CD4 count of < 500 (1- 5years) and < 200 (6-12 years). All children who have been treated for PCP.
TABLE – 3
Drug Schedule Side Effect
TMP-SMX • 150 mg of TMP/M2/day. Orally in two divided doses on 3 consecutive days of a week.
• 150 mg of TMP/M2/ day orally divided into 2 doses on 3 alternating days. Aplastic anaemia megaloblastic anaemia, Steven – Johnson’s Syndrome, Neutropenia, Thrombocytopenia
Dapsone 2mg/Kg/Day orally
(Max – 100mg) Methemoglobinemia
Haemolytic anaemia
Pentamidine (inhaled) 300mg of Pentamidine isoethionate inhaler every 28 days Cough, bronchospasm , increased risk of extra pulmonary PCP
Pentamidine (I/V) 4 mg/Kg /Day single dose I/V every 2-4 weeks Hypoglycemia, Hyperglycemia, Hypertension, Hypocalcaemia, rash

Rhodococcus Equi – Gram +ve pleomorphic acid – fast nonspore forming bacillus causing pulmonary or /and disseminated infection. Presents as fever cough. Chest X-ray show cavity or consolidation. Blood culture may be +ve treated with proper antibiotic.

TUBERCULOSIS:
In high prevalent areas primary and reactivation of tuberculosis is common due to depressed cell mediated immunity. Drug resistance is also common. The extensive tuberculosis is due to progressive depletion and dysfunction of CD4 cells with macrophage and monocyte dysfunction.

Clinically present as fever, cough, weight loss, night sweat, malaise. Extrapulmonary manifestation like CNS (meningitis), lymphadenopathy, hepatosplenomegaly, genitourinary, mastoid involvement occur. The disease may be extensive (miliary).

Diagnostic difficulty is due to unusual features (Tuberculin – ve) and extrapulmonary manifestation. History of contact, tuberculin test (induration > 5 mm), chest X-ray showing lobar or multilobar infiltration or diffuse interstitial lesion and hilar adenopathy are clue. Isolation of AFB from gastric lavage, BAL, sputum is gold standard test. The samples collected from pulmonary and extrapulmonary tissue subjected to culture and sensitivity to drugs as drug resistance is very high. PCR test on sputum , pleural fluid, CSF is highly sensitive and specific.

Treatment:
1st Line Drugs:
INH – 10-20 mg/kg/day (max 300mg)
Rifampicin – 10-20 mg/kg/day (max 600mg) – (May lower the concentration of antiretroviral drugs as it induces the action of hepatic cytochrome 450).
Pyrizinamide - 30 mg/kg/day
Ethambutol - 15 mg/kg/day
Streptomycin – 20-30 mg/kg/day IM
Rifabutin – 300mg for 4 months
2nd Line Drugs:
Ofloxacin, Ethionamide, Cycloserine, Capreomycin, PAS

Duration of Treatment:
• For pulmonary TB – 6-12 Months
• For extrapulmonary TB – Minimum 12 Months
• DOT (Directly Observed Therapy) may be given during initial phase.
• Children of Mx positive without any other lesion – INH & Rifampicin for 12 months.
• In MDR TB – 6-7 drugs depending on sensitivity for 12-15 months.
To start ART the CD4 count is a guideline (WHO recommendation).
• CD4 count < 200/L – Start ATT first and ART is started as soon as patient tolerate ATT (Takes 2-4 weeks).
• CD4 count 200 to 350/L – Start ATT and add ART after intensive phase –(8weeks).
• CD4 count > 350/L – Treat TB completely and defer ART.

NON-TUBERCULOSIS MYCOBACTERIAL INFECTIONS
Mycobaacterium avium complex (MAC) includes M. kansasii, M. Chelonei and M. fortuitum which are saprophytes present in soil, water, food and infect when CD4 count is below 50 cells/ml. Lung, liver, spleen and lymphnodes, bone marrow and GIT are the common sites. Incidence is less in India. Transmitted by inhalation or ingestion. Lung is an unusual site of infection.

Slow progressive clinically present as high fever, weight loss, anemia, abdominal pain, night sweat, diarrhoea, malaise, hepatomegaly, osteomyelitis, meningoencephalitis, intraabdominal and soft tissue abscesses.

Peripheral smear shows anaemia, neutropenia, chest X-ray shows nonspecific finding like focal, diffuse infiltration, cavity, hilar adenopathy. Culture of blood or tissue by Radiometric assay show +ve in two weeks. PCR can identify the species. Biopsy from liver, L. node or marrow shows AFB bacillus within macrophages.

For treatment Azithromycin (10 mg /kg/day – single dose), Clarithromycin (15 mg /kg/day – 2 divided dosees), Ethambutol (15-20 mg /kg/day – single dose), Rifabutin (5-10 mg /kg/day – single dose) Ciprofloxacin (20-30 mg /kg/day Orally– single dose) Amikacin are given. The regimen includes 2-4 drugs i.e Azithromycin or Clarithromycin with Ethambutol and/or Rifabutin and Ciprofloxacin or Amikacin. Immunomodulators like GM-CSF, G-CSF, Interferon gamma, interleukin –2 are helpful.

For primary prophylaxis any drug is given for periods depending on CD4 count (< 50 – 6years, <75 2 –6 years, < 500 – 1-2 years, < 750 – 12 months). Secondary prophylaxis in patients suffering from MAC is life long including at least two drugs.

TOXOPLASMA GONDII INFECTION
In children manifest as congenital toxoplasmosis and CNS manifestation. Pregnant Mother transmit to fetus.

Congenital toxoplasmosis present as low birth weight, microcephaly, hydrocephalus, hepatosplenomegaly and chorioretinitis. CNS toxoplasmosis present as fever, headache, seizures, psychosis, altered sensorium and focal meurological deficit as hemiparesis, ataxia, cranial nerve palsy, aphasia, cerebral edema, confusion, dementia, coma.
Demonstration of specific IgM and IgA antibodies in serum is diagnostic of congenital toxoplasmosis. CNS toxoplasmosis is diagnosed on clinical ground, presence of IgG antibodies and multiple ring enhancing granulomatous lesion on CT scan or MRI. Brain biopsy is definitive diagnosis.

TREATMENT
Sulphadiazine – Loading 100mg/kg followed by 85-120mg /kg/day in 2-4 divided doses. Pyrimethamine – 1-2 mg /kg/day for 2 days followed by 1 mg/kg/day for 2-6 months and 1 mg /kg/day up to 1 year. Folinic acid (calcium leukovorin) 5-10 mg /kg/day or alt days to prevent megaloblastic anaemia secondary to pyrimethamine. Prednisolone 1 mg/kg/daily orally in active chorioretinitis or CSF protein is > 1gm%. Clinadmycin (20 mg/kg/day in 4 divided doses), pyrimethamine, folinic acid is alternate regimen.
CNS Toxoplasmosis: - The drugs used are pyrimethamine and sulfadiazine or Trisulfapyrimidine. Folinic acid is given to prevent bone marrow suppression. Relapse is common which requires reinstitution of therapy.
An episode of CNS toxoplasmosis requires life long prophylaxis.

VIRAL INFECTIONS
The common viruses are Herpes Simplex Virus (HSV 1 & 2), Cytomegalo Virus (CMV), Varicella Zoster Virus (VZV), Epstein Barr Virus (EBV) and Human Herpes Virus type – 8 (HHV-8). The infections are often chronic, invasive and fatal with HIV infection.
1. HSV 1 & 2: HSV-1 is transmitted through contact with oral mucosa and salivary secretions. HSV2 transmitted sexually and present as anogenital lesion. When CD4 count is > 100/mm3 both present as recurrent self-limited cluster of orolabial ulcers, genital, anorectal ulcers. In lower CD4 count the vesicular lesions are found at other sites. In severe cases there are large, painful ulcer which slowly resolve. Stomatitis follow oral lesions and fissures and fistula follow rectal and genital ulcers. Bacterial infection may supervene. Advanced AIDS cases with low CD4 count may produce systemic HSV-infection producing oesophageal ulcer (odynophagia, chest pain)pneumonia, hepatitis, meningoencephalitis, ventriculitis, shock, sepsis like syndrome and transverse myelitis.
Diagnosis is based on typical clinical lesion, rising antibody titre, isolation of virus from culture, detecting HSV1 & 2 antigen from skin or mucosa by scraping and immunofluorescent stain. In suspected HSV encephalitis HSV DNA in CSF using PCR is useful.
Acyclovir is drug of choice. In neonates and severe HSV infection given in a dose of 30 mg/kg/day in 3 divided doses for 2-3 weeks. Primary gingivostomatitis or genital HSV are treated with oral Acyclovir 80mg/kg/day in 3 divided doses for 10 days. Famcyclovir or Valacyclovir in a dose of 750- 1500 mg/day in 3 divided dose may be used. Foscarnet in a dose of 120mg/kg/day on 2-3 divided doses in Acyclovir resistant cases.
For prophylaxis in HIV patients with frequent or severe relapse or slow healing lesion Acyclovir 200mg tid or 400mg bid orally is given.
2. Vericella Zoster Virus (VZV):
In immunocompromised patients causes greater morbidity and mortality. Clinically presents as fever with generalized pruritic rashes (typical). They may be chronic, recurrent, persistent (appearance of new lesion for > 1 month), sever in advanced cases. In chronic infection the skin lesion become verrucous or necrotic. In severe infection presents as high fever, numerous skin lesion, systemic involvement like pneumonia, encephalitis, hepatitis.
Demonstration of VZV antigen in skin lesion, isolation of virus from vesicle contents, rise in antibody during convalescence and VZV specific IgM antibody confirm the diagnosis. PCR is also extremely sensitive and specific.
In severe cases Acyclovir in a dose of 1500mg /M2/day in 3 divided doses for 7-10 days or till no new lesions appear whichever is later is given. In mild cases Acyclovir is given orally 80mg/kg/day in 4 divided doses.
HIV infected children exposed to chickenpox are given varicella zoster immunoglobulin (VZIM) within 96 hours in a dose of 1 vial/10kg (maximum 5 vials). For recurrent case daily Acyclovir is given.
3. Herpes Zoster:
It is a dormant form of VZV producing painful vesicular lesion affecting dermatomes in immunocompetent persons.
Clinically presents as multidermatomal infection, dessiminated Zoster, bilateral rash, retinitis, rarely penumonitis, consumptive coagulopathy, hepatitis, marked constitutional symptoms and encephalitis. Chronic and relapsing cases and post herpetic neuralgia are common.
Classical dermatomal distribution of painful, vesicular eruption is diagnostic. Confirmed by virus isolation and detection of viral antigen in the skin.
Severe cases or neurologic complications like Ramsey Hunt, Zoster Ophthalmicus, disseminated zoster require Acyclovir 30mg/kg/day in 3 doses I/V. Oral Acyclovir 80mg/kg/day in 4 divided doses hastens healing. Famciclovir and Foscarnet are drugs used in resistant or recurrent cases.

4. Cytomegalo Virus (CMV)
It is very common OIs and carry poor prognosis. Horizontally transmitted through saliva, sexual fluid, urines and vertically by infected mother. More than 90% of HIV pregnant mother are CMV – infected.
Clinical manifestations:-
a. Retinitis: - Chorioretinitis develops in CMV seropositive cases when CD4 count is < 50 cells/l. Blurred vision, floaters and flashes are nonspecific symptoms, which starts with one eye progressing to other. It is painless. It leads to visual loss and retinal detachment. Yellowish white area of retinal necrosis with perivascular exudates and haemorrhage at periphery is characteristic.
b. GI Manifestation :- Oesophagitis produce substernal pain, dysphagia and anorexia, Colonic involvement cuase diarrhoea, abdominal pain, weight loss , anorexia, fever, CMV hepatitis and gastritis are uncommon. In 5-10% cases of AIDs cause colitis.
c. Penumonitis – Cough, dyspnoea, hypoxaemia
d. Encephalitis – Produce sub-acute dementia complex.
Diagnosis:- Retinitis is diagnosed by Fundoscopy. GIT infections on mucosal biopsy shows inflammation and CMV inclusion bodies. On endoscopy oesophagitis shows small and confluent ulcers. Sigmoidoscopy of colon shows diffuse erythmatic, submucosal haemorrhage and multiple mucosal ulcer. Chest X-ray of pnumonitis shows diffuse interstitial infiltration and finding of inclusion bodies in lung tissues or BAL is supportive.

Serological test for CMV are less helpful.
Treatment: Ganciclovir 10mg/kg/day in 2 divided doses I/V over 2 hours for 14-21 days followed by life long maintenance therapy.
Or
Foscarnet – 180mg/kg/day in 3 divided doses I/V over 1-2 hours for 14-21 days followed by life long maintenance therapy with 90-120mg/kg/IV in a single daily dose.
Prophylaxis :- Regualr retinal examination at 4 – 6 weeks interval. Life long prophylaxis with Ganciclovir 5mg/kg/day IV 5 days per week.

Other viral infections:
1. Human Herpes Virus – 8 (HHV – 8): This DNA virus causes Kaposi sarcoma in seropositive cases. Although Ganciclovir , Foscarnet, Cidofovir are active in vitro their use in limited.
2. Progressive multifocal leukoencephalopathy by JC Virus : This is caused by polyoma Virus JC virus. Insidious onset with progressive features like congnitive dysfunction, dementia, seizure, ataxia, aphasia, cranial nerve palsy, hemiparesis, quadriparesis, Coma. CT scan shows single or multiple hypodense, non-enhancing lesion in cerebral, white matter. Confirmed by biopsy. No effective treatment. Majority dies within 3-6 months of symptoms.
3. Human Papilloma Virus (HPV): - Infection in anogenital tract resulting in transient infection, genital wart, condyloma, squamous cell cancer. Dignosed clinically and biopsy. No effective treatment.
4. Hepatitis C Virus (HCV): - High rate of HCV coinfection in HIV- I persons through drug user injection, mother to child or sexual route. HIV – I infection increases the progress of HCV infection leading to end stage liver disease. Acute HCV infection is symptomatic or mild symptomatic. Chronic infection leads to hepatocellular failure. A progressive form called fibrosing cholestatic hepatitis found in HIV- I infection. Anti viral treatment is considered in chronic HCV infection. Avoid alcohol. Two doses of Hepatitis A vaccination is advised.
5. Hepatitis B Virus (HBV): About 90% of HIV – I patients are +ve for some markers of HBV. It is associated with increased risk of chronic HBV. Symptoms of acute infection are nausea, vomiting, jaundice, abdominal pain, Chronic infection presents as fatigue hepatocellular failure. Testing for HBs Ag, Anti HBc, Anti-HBs are used. Detection of HBs Ag  6 months is chronic and should be tested for HbeAg and Antigen HBe. They are increased risk of carcinoma.
Avoid alcohol – Two doses of Hepatitis A vaccination and 3 doses of Hepatitis B vaccination is given. Antiviral treatment is given.
6. Hepatitis A Virus (HAV) – All susceptible, chronic HCV cases. Two doses of Hepatitis A vaccination given. Not seen so frequently
7. Influenza virus : All patients annually – inactivated trivalent influenca virus vaccine – 1 dose yearly. Oseltamivir – 75 mg orally – 4 tims or Rimantidine /Amantidine – 100 mg orally – 4 times are used.
8. EBV – When CD4 is < 300L cause oral hairy leukoplakia along tongue border and adjacent mucosa. Not a premalignant condition. Treated with topical podophyllin or systemic antiherpes virus infection.
9. Coinfection with hepatitis D, E, and G are also common.

Cryptosporidiosis: Protozoa parasite . Infects small and large gut and extra intestinal. In this group C.hominis (previously C. parvum) C. canis, C. felis, C. muris. C. meleagridis . Biliary tract involvement like papillary stenosis, sclerosing cholangitis are seen.
Microsporidiosis: Protists related to fungus, contains several groups of organism. Water borne in origin. Commonly manifest as diarrhoea. Rarely encephalitis, sinusitis, ocular manifestation, myositis and disseminated infection occur.
Bartonellosis: Bacterial infection causing Bacillary angiomatosis of skin. Organisms are B. henselae, B. quintana and others. Common among poor sanitation. Common when CD4 count is < 50 cells and chronic infection involving every organ but typical skin lesion which is papular, red, smooth surface, vascular and bleed on trauma. Diagnosed by biopsy. Serological test may be +ve before clinical disease. Treated with Erythromycin /Doxycycline/ Clarithromycin/Azithromycin for at least 3 months.
Syphilis: The impact of HIV – I infection on syphillis (Treponema pallidum) pathogenesis, severity , response to treatment and long term sequelae is not well documented. However the progress is hastened in immunocompromised state. A variety of rare presentation like lues maligna, an ulcer due to necrotising vasculitis. Most commonly presented as condylomata lata. VDRL is of ambiguous significance.
FUNGAL INFECTION:
A. Cryptococcal Infection: Cryptococcus neoformans – infects when CD4 count is <50. This unusual disease involves brain, meninges, skin, eye. Clinically may present as meningitis, meningoencephalitis. Pneumonia is seen in 50% of cases. Sepsis though rare is fatal. Post infective sequlae like hydrocephalus, seizure, ataxia, cranial nerve involvement is common. Uncommon presentation may be in skin (Molluscum contagiosum), L. node enlargement, palatal, glossal ulcer, myocarditis, prostitis, gastroenteritis.
In CSF fungus is detected by India ink stain, cryptococcal antigen (95-100% specificity and sensitivity), positive culture. A positive latex agglutination test from seum also used in pulmonary cases. CT Scan of brain may show granuloma (cryptococcomas). Chest X-ray may show poorly localized bronchopneumonia, nodular or lobar involvement, pleural effusion , hilar, mediastinal adenopathy.
Amphotericin B ( 0.5 – 1 mg/kg/day IV , once daily) with or without Flucytosine (50-150 mg/kg/day orally in 4 divided doses) for 14 days until clinical improvement is initial treatment. Fluconazole (6-12 mg/kg/day, orally) or Itraconazole (2-5 mg/kg/day, orally) up to 8-10 weeks is follow up therapy. Life long secondary prophylaxis with Fluconazole or Itraconazole or Amphotericin B is required.
B. Histoplasmosis: Dimorphic fungus Histoplasma capsulatum. By inhalation or reactivation of latent infection. Manifest as disseminated multiorgan disease – fever, fatigue, weight loss, respiratory symptoms. CNS, GIT, Skin Manifestation seen in < 10% of cases. Diagnosed by presence of antigen in serum or urine, fungal stain of blood or tissues. Chest X-ray in 50% show diffuse interstitial infiltration or diffuse nodularity. Bone marrow involvement is common causing anaemia, neutropenia, thrombocytopenia. Treated by Amphotericin-B 1mg/kg/daily followed by Iatraconazole.

C. Coccidioidomycosis: By C. immitis causing disseminated diseases or meningitis. Dissemianted present as generalized lymphadenopathy, skin nodule or ulcer, peritonitis, liver, bone and joint involvement. Local meningitis is 10% of cases. Diagnosed by culture or serology of serum or CSF. Pulmonary (nodules, cavity, pleural effusion, hilar adenopathy) and disseminated form is treated with Amphotericin B and meningitis is treated with Fluconazole.
D. Aspergillosis: By Aspegillus fumigatus causing two syndromes – Respiratory (pseudomembranous tracheitis, penumonitis), CNS infection (meningoencephalitis with vascular infarction). Diagnosed clinically and demonstration of organism. Treated with Amphotericin B or Variconazole.
E. Candida Infection: Oral candidiasis (thrush) and diaper skin are common. Thrush may be extensive. Painless, creamy white plaques over buccal , oropharyngeal, or tongue which can be easily scrapped off. Angular chelosis may be seen. Oesophageal candidiasis may present as substernal or abdominal pain, dysphagia, weight loss. Disseminated infection present as sepsis or shock. Vulvovaginal candidiasis present as creamy to white yellow vaginal discharge with mucosal burning or itching, dysuria, dysparenia. Vaginitis may be due to trichomonas or bacterias also.
Oral candidiasis are typical and confirmed by presence of pesudohyphae on KOH stained specimen. Oesophageal involvement is diagnosed by clinical, endoscopy and biopsy. Blood culture may be +ve.
For oral candidiasis Nystatin, Amphotericin-B and Azoles are used. Oral Azoles are used when topical application fails. For oesophageal candidiasis. Fluconazole and for disseminated Amphotericin B is the choice.
TABLE
Condition Drug Dose & Duration
Oral Candidiases • Nystatin – Suspension, Lozenge
• Amphotericine B oral Suspension
• Clotrimazole
• Fluconazole
• Ketoconazole
• Itraconazole • 1-2 Lak U orally 4 times – 14 day
• 1 mg orally 4 time – 14 day
• 10mg orally 4 times – 14 day
• 3-6 mg/kg orally once – 14 day
• 5-10mg/kg Orally once – 14 day
• 2-5 mg/kg Orally once – 14 day
Esophageal Candidiasis • Fluconazole
• Itraconazole
• Amphotericine – B • As Above
• As Above
• 0.5 – 1 mg/kg/daily IV – 14 days
Disseminated Candidiasis • Amphotericine – B • As Above

Oral Fluconazole is given as prophylaxis is recurrent cases.
E. Other Fungus: Cause meningoencephalitis – Naegleria, Achanthamoeba.

DERMATOLOGIC DISORDERS:
Seborrheic Dermatitis: Seen in 50% of HIV cases. Aggravated by Pityrosporium , a yeast like fungus. Ttopical antifungal treatment is useful.
Eosinophillic pustular folliculitis: Multiple urticarial perifollicualr papules associated with mite infection which respond to topical anthelminthics.
Norwegian scabies: Hyperketatotic psoriasiform lesion.
VZV: Reactivation in 20% cases of HIV, Visceral involvement is rare. Involve several dermatomes Acyclovir, Famciclovir, Foscarnet are used.
HSV: Recurrent oroabial, genital, perianal lesion as part of reactivation. Perirectal is associated with proctotis.
Molluscum Contagiosum: Flesh coloured umbilicated lesion, regress with ARV.
Erythematous Nodules: Due to Atypical microbacteria, fungus, bartonella, Aconthamoeba.

OPHTHALMIC DISEASES:
CMV retinitis: Painless, progressive visual loss with blurred vision. Retina shows perivascualr haemorrhage and exudates.
HSV & VSV: May cause bilateral necrosizing retinitis called Acute Retinal Necrosis Syndrome or Progressive Outer Retinal Necrosis (PORN). There is pain, keratitis, iritis , associated with orolabial HSV or trigeminal zoaster. Fundus shows pale gray periphery. Complicated by retinal detachment.
Other infections: P. carinii- Choroid lesion- Bilateral elevated yellow white plaque. Toxoplasma – Chorioretinitis associated with CNS lesion.

RECURRENT BACTERIAL INFECTIONS:
Recurrent bacterial infections within 2 years period is peculiar to HIV patients. The clinical presentation depends on the system involved.

TABLE
Site of infection Common Organism Clinical Manifestation Diagnostic Evaluation
Meningitis S. penumonia
H. influenzae
N. meningitides Fever, Headache, Vomiting, Altered sensorium, Neck rigidity CSF – examination and culture
Pneumonia S. penumonia
H. influenzae
Ps.aeruginosa
N. aosteroides Fever, cough, chest pain, tachypnea, crepitation Chest X-ray, Sputum Culture
Bacteremia S. penumonia
H. influenzae
Salmonella species Fever Or Hypothermia , Features of Multiorgan Dysfucntion Blood Culture
Oesteomyelitis Staphylococci Fever, pain, swelling or redness at local site Bone scan, Radiograph
Sinusitis S. penumonia
H. influenzae Persistent nasal discharge , fever, cough, Maxillary sinus – common Radiograph
Central venous catheter infection Staph aureus & epidermidis.
K. penumonae
Acinetonbacter species
Pseudomonas Species Redness and tenderness at local site Culture
Skin, ear and upper respiratory tract S. penumonia
H. influenzae
Group A beta fever, Haemolytic URTI Skin- Pyoderma
Ear- Pain, Discharge
URTI- Cough Culture from specimen

Treatment depends on culture sensitivity. Empiric broad spectrum antibiotic may be started taking into account the site of infection, nuetropenia, in dwelling catheter and other risk factors.

For prophylaxis immunization against organism and proper hygiene is to be maintained. Daily TMP-SMX may be used. Intervenous immunoglobulin monthly may boost the immunity.


DIARRHOEA:
Chronic diarrhoea is very common, which may be due to various organisms and side effects of drugs.
TABLE
Organism Species
Bacteria Salmonella, Shigella, Campylobacter, Clostridium difficile & MAC
Virus CMV, Adenovirus, HIV, HSV, Rota Virus
Protozoa Isopora belli, Cryptosporidium parvum, Microsporidia, E. histolytica, G. lamblia, Cyclospora
Fungi Histoplasma, Coccidiodomycosis, Penicilliosis

Peritonitis is seen in C.immitis.
Clinically presents as large watery stool, abdominal pain associated with fever, dehydration, anorexia, wasting and cachexia. Biliary tract involvement (cholangitis, cholecystitis) is seen in Isospora, Microsporidium, Cryptosporidium and Cyclospora.

DIAGNOSIS AND TREATMENT
Organism Diagnosis Treatment
Isospora Oocyst in stool after acid fast stain TMP SMX – 3-4 weeks Pyrimethamine with folinic acid
Cyclospora Oocyst in stool in acid fast stain Orally TMP SMX for 7 days
Microsporidia
Examiantion of concentrated stool,small intestine biopsy on EM or PCR Albendazole
Cryptosporidium
Stool examination in acid fast stain, Immunoflucoscent assay and stool ELISA Fluid supplementation, Paramomycin- Spiramycin, Azithromycin, Clarithromycin
E. histolytica Stool , trophozoite & Cyst, Serological test - +ve with tissue invasion, Endoscopy and biopsy For gut – Iodoquinol, diloxanide furoate, paramomycin
Invasive – Metronidazole, Dehydrometine
Hepatic – Chloroquine
G. lamblia Trophozoite and cyst in stool or duodenal aspirate, Giardia antigen in stool Metronidazole, Furazolidine, Tinidazole
Adenovirus Sigmoidoscopy – Patchy erythema & raised white lesion
Mucosal Biopsy – Intranuclear inclusion , Virus may grow Supportive treatment
Rotavirus ELISA in stool sample Supportive treatment
Camphylobacter Stool culture or blood culture.
Immunological test – IF, LA
Serology – ELISA for IgG, IgM, IgA level Azithromycin, Clarithromycin, Erythromycin, Ciporfloxacin, supportive therapy
Shigella Endoscopy – Deep mucosal ulcer and pseudomembrane
Stool Culture Ampicillin , cefixime, ceftriazone, Quinolones, Supportive care
Salmonella Stool Culture
LA and Fluorescence test
PCR Duration of treatment is 14 days
Cefotaxime /Ceftriaxone, Ciprofloxacin
Cl. difficile Stool Examination
Toxins detected by ELISA Supportive
Metronidazole
Vancomycin

Special Geographical OIs:
1. Penicilliosis: By dimorphic fungus Penicillium marneffei seen in Thailand, China. Infect when CD4 is less than 50 and high mortality if untreated. Presents as fever, weight loss, with skin, lymph node, bone marrow and hepatic involvement. Cutaneous lesions are papullar with central umbilication over face, ears and extremities. Fungus can be demonstrated. Treated with Amphotericin B for 2 weeks followed by Itraconazole for 10 weeks.
2. Leishmaniasis: It is an obligatory intracellular protozoa seen worldwide. May present as localized or diffuse cutaneous, mucosal or visceral disease, the last being common in AIDS (70%). Demonstration of Leishmania from lesion and antibody is diagnostic. Treated with pentavalent antimony.
3. Paracoccidiodomycosis: Dimorphic fungus P. brasiliensis, seen in central and South American. Few cases in HIV – I presenting multisystemic involvement. Treated with Amphotericin B or Azoles.
4. Isosporiasis: the Protozoa I.belli present in Caribbean & Africa and Worldwide. Presents as diarrhoea with systemic symptoms of fever, weight loss, abdominal pain. Treatment is supportive. Pyrimethamine or TMP-SMX are tried.
5. Chaga’s disease (American Trypanosomiasis): A flagellated protozoa T. cruzi. Among HIV-I infected persons with immunosuppression the reactivation is increased. Present as fever, headache, vomiting, seizure. Single or multiple ring enhancement in subcortical area (Vs toxoplasma – deeper). CSF may show increased cell and proteins. Organism found in blood or tissue. Treated with Benzimidazole (2.5 mg/kg BID) or Nifurtimox ( 2 mg/kg/QID) for 60 days followed by maintenance therapy for life with either drug in a dose of 5 mg /kg thrice a week.
6. Microsporidia: Small unicellular, obligate intracellular parasite, reside in the cytoplasm of enteric cells. The main species is Enterocytozoon bieneusi. Detected by light microscope with chromotobe bases stain. E/M of stain. In contrast to cryptococcal it is seen in other tissue like eye, muscle, liver . Albendazole is treatment.
7. Cryptosporidia: Symptoms range from self limiting, intermittent to sever life threatening diarrhoea. Assoiciated with nausea, vomiting, crampy abdominal pain. Associated with cholangitis and cholecystitis. Diarrhoea is non-inflammatory. Stool containing occyst stain with acid fast.

SUMMARY
• Opportunistic infections due to various organism are associated with HIV infection at some stage or other.
• They can be classified depending on the CD4 count or system involved.
• PCP is commonest form of pneumonia though there is a six-fold rise of pneumonia incidence due to other bacterias.
• The incidence, complications and resistance of M. tuberculosis is more in HIV cases. ATT is modified according to immune status of the patient.
• Atypical mycobacteria specially MAC incidence is common.
• Toxoplasma gondii infection of CNS leads to various clinical presentation.
• The common viral infections are HSV, CMV, VZV, EBV, HBV and HCV. CMV products commonly retinitis and GI complications.
• Fungal infections like candida, cryptococcal and histoplasma are common producing various complications.
• Dermatological and Ophthalmic complication due to various infections are vary often encountered.
• Due to low immune status recurrent bacterial infections give rise to varied clinical manifestations.
• Chronic diarrhoea due to multiple microogransim is a constant problem.
• Depending on the geographical distribution of some organism the infection predominantly seen.

CONCLUSION

With high prevalence of AIDS in developing and underdeveloped Countries the risk of OIs due to organisms is a menance. The clinical presentations are quite different than normal host. Wherever possible attempts are to be made to obtain tissue or specimen to establish a definitive diagnosis. Various studies have proved the relation between CD4 count and progression of HIV and OIs. Timely diagnosis and treatment and chemoprophylaxis have reduced the mortality and morbidity. Additional ART successfully decreases the organism load and restores the immune function reducing the development of OIs.

CLINICAL FOCUS
• OIs due to various microorganism go hand in hand with infection.
• The clinical presentation somewhat differ from normal host.
• Depending of CD4 count the HIV related infections are different.
• PCP is commonest infection in children and adult having high fatality if untreated.
• Depressing cellular immunity is responsible for high incidence of tubercular infection where the treatment modality depends on CD4 count.
• Atypical mycobacteria specially MAC is quite common giving rise to various systemic complications.
• Toxoplasma infection is another treatable neurological infection.
• Various viral infections are common out of which CMV carry poor prognosis as it involves multisystems.
• EBV produces hairycell leukoplakia.
• Incidence of HBV is about 90% of HIV cases,
• Fungal infections like Cryptococcus, Histoplasma present as disseminated multiorgan disease.
• Oral, oesophageal and vulvovaginal candidiasis are common and can be properly treated.
• CMV retinitis causes progressive permanent blindness.
• Recurrent bacterial infections are common giving rise tp various diseases.
• Chronic diarrhoea is very common, due to organism or drugs.


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Jul22
TUBERCULOUS MENINGITIS
INTRODUCTION
Neurological Tuberculosis comprises 10 to 15% of cases of extrapulmonary tuberculosis and occur frequently in children. Tuberculous meningitis (TBM) accounts for 70 to 80% of cases of neurological tuberculosis. It is common in developing countires, including India. A delay in diagnosis and treatment results in fatal outcome. So physician’s responsibility rests on the promptness of instituting adequate therapy considering the predisposing factors, proper diagnosis by adopting various diagnostic methods, associated conditions, treatment of complications and prevention. The resurgence of tuberculosis in industrialized modern India with HIV epidemic , atypical clinical presentation and increase in multidrug resistant tuberculosis (MDR – TB) is a significant health problem.

PATHOGENESIS
The Organism responsible is commonly Mycobacterium tuberculosis. Rarely M. boovis, M. avium, M. ulcerans, M. africans, M. intracellular are documented to cause meningitis.

The observation of pathogenesis discussed by Mc Cordock and Rich are still accepted . The CNS involvement occurs in a stepwise manner. In the bacteraemic phase of primary lung infection the metastatic foci get established in the subependyma (RICH-FOCUS) like seedling in any other organ. It is still a dispute that the subependymal foci may develop during primary lung infection or due to secondary haematogenous spread from extracranial extrapulmonary site. Then after a latent phase varying from weeks to years a stimulus , either immune or trauma leads to release of organism and antigen contained in the tubercle to the subarachnoid space causing the disease.

Conditions which lead to reactivation are intercurrent viral infection, advanced age, alcoholism, malnutrition, corticosteroid use, immunosuppresant drugs, HIV infection and other immunocompromised status. However in most cases no such condition may be found.

PATHOLOGY
The pathological process involves various intracranial tissues leading to multifarious presentation.
TABLE – I
A. Meningitis Inflammatory leptomeningeal exudates
Caseous necrosis
Proiferative opticochiasmatic arachnoiditis
B. Vasculitis Arteritis
Phlebitis
C. Ependymitis and choroids plexitis
D. Encephalitis Cotical
Subepedymal
Vasculitis and infarction
Tuberculosis encephalopathy
E. Disturbance of CSF circulation and absorption (Hydrocephalus) Communicatiing
Obstructive

Serofibrinous exclude collect between pia and arachnoid intermixed with caseous necrosis. The exudates contain mainly lymphocytes and plasma cells with few giant and epitheloid cells. Mycobacteria are present in variable number. Anti TB treatment induces further caseation of the exudates. With successful treatment the exudates resolve leaving residual tubercles, foci of caseation and fibrosis. Proliferative arachnoiditis commonly at the base of the brain involve the area of optic chiasma. As the process becomes chronic it encircles the brain stem involving other cranial nerves.

The terminal portion of internal carotid artery and proximal middle cerebral artery in the Sylvian fissure are commonly involved by vasculitis with inflammation, spasm, constriction and thrombosis. Inflammatory cells infiltrate all layers of vessels and tubercles form first in advertitia and then in media and intima. With progress the media layer fibrose, the intima thickens and vessel lumen shrinks in a necrotising vasculitis reminiscent of periarteritis nodosa. The meningeal veins traversing the inflammatory exudates show varying degrees of phlebitis and thrombosis.

Ependymitis is always a feature of TBM and becomes more severe than meningeal reaction. The choroids plexus shows varying degree of inflammation.

The brain parenchyma underlying the meningeal exudate and subepednymal region show variable degree of oedema, perivascular inflammation and microloglial reaction. Infarction occurs in the territory of middle cerebral artery. Occasionally diffuse cerebral oedema, demyelination and haemorrhagic leukoencephalopathy are identified, mostly in children, attributed due to hypersensitivity reaction to tuberculoproteins. Atrophy of gray and white maters are induced by hydrocephalus .

Hydrocephalus develops in most symptomatic cases within 2-3 weeks. Commonly it is communicating type due to blockage of the basal cistern by exudates in acute stage or adhesive leptomeningitis in chronic. Less commonly it is obstructive type due to narrowing or occlusion of aqueduct by ependymal inflammation or tuberculoma or due to obstruction at the outlet foramina of 4th ventricle. Hydrocephalus is common and severe in children than adult.

CLINICAL FEATURES
The clinical manifestations of TBM are protean. The presentation varies in different series and countries. The most determinant factor is age. In developing countries TBM is disease of childhood with highest incidence in first 3 years of life. The disease is usually a subacute or chronic onset, rarely acute (Children – 50%, Adult 14%). A history of TB can be elicited in child (50%) and adult (10%).

History of lowering resistance like bacterial or viral infection may be elicited. The disease evolves over 2-6 weeks. The prodromal phase lasting for 2-3 weeks may have vague ill health, apathy, irritability, anorexia and behavioral changes. With onset of meningitis headache , vomiting and fever occur. Focal neurological deficit and features of raised intracranial pressure (papilloedema) may preceed meningitis. Convulsion (focal or generalized) are seen in 20-30% cases during course. Cranial nerve palsies occur in 20-30% (commonly 6th cranial nerve). Complete or partial loss of vision is a major complication. The contributing factors for visual impairment are opticochiasmatic exudate, arteritis, hydrocephalus or tuberculoma compressing anterior visual pathway and Ethambutol toxicity. Other clinical presentation may be hemiplegia, facial nerve palsy, optic atrophy, abnormal movement, oculomotor nerve palsy and choroid tubercles.
In untreated cases consciousness deteriorate, pupillary abnormalities and pyramidal signs are seen due to increasing hydrocephalus and tentorial herniation. Terminally deep coma, decerebrate or decorticate posture occur. Without treatment death occurs in 5-8 weeks.

According to severity and neurological findings TBM is categorized into 4 stages which is useful for treatment and prognosis.
TABLE – 2:CLINICAL STAGING OF TBM
Stage Symptoms & Signs
I Conscious and rational , with or without neck stiffness
No focal neurological sign or hydrocephalus
Other nonspecific symptoms
II Conscious but confused or has focal signs like cranial nerve palsy or hemiparesis
Signs of meningitis
III Comatose or delirious with or without dense neurological signs. Systemic toxicity . Gross paralysis , seizure, abnormal movements.
IV Deeply comatose with decerebrate or decorticate posture.

The paresis reflects ischemic infarction from vasculitis. It may be induced or exacerbated by hydrocephalus.

The picture of TBM has changed in some developed countries with atypical presentation like acute meningitis syndrome, progressive dementia, status epilepticus, psychosis, stroke syndrome, locked in state, trigeminal neuralgia, infantile spasm and movement disorder. The factors responsible are delay in the age of onset of primary infection, immunization, immigrant population and HIV infection.

HIV infection – CNS involvement are 5 times more in HIV + patients . HIV status does not alter the clinical manifestions, CSF findings and response to ATT. It has been observed that intravenous drug abusers having AIDS exhibit increased risk of CNS tuberculosis and tubercular brain abscess.

DIFFERENTIAL DIAGNOSIS:
TBM should be differentiated from other conditions of subacute or chronic meningitis.
TABLE – 3 Differential Diagnosis of TBM
. Partially - treated bacterial meningitis
. Cryptococcal meningitis
. Viral meningoencephalitis
. Carcinomatous meningitis
. Parameningeal infection
. Neurosarcoidosis
. Neurosyphilis
. Other infections due to Treponema, Brucella, Leptospirae
. Fungal infections due to Candida, Histoplasma, Aspergillus, Actinomyces
. Non infection causes due to systemic lupus erythematous, connective tissue disorder, Bechets disease, chronic benign lymphocytic meningitiss, drugs and chemicals (lodophendylate dye, Sulphonamide /Ibuprofen, Tolmentin)

Diagnosis of TBM is fraught with difficulties as demonstration of M. tuberculosis in CSF is difficult and time consuming. Diagnosis is based on neurological symptoms and signs, CSF findings, radiological evidence of exudate, hydrocephalus, infarction, tuberculoma. Evidence of tuberculosis outside CNS with positive Mantoux test, history of contact and response to treatment are supportive features of tuberculosis etiology.

DIAGNOSIS - BASED ON VARIOUS TESTS:

1. ROUTINE TESTS: Rarely helpful to establish diagnosis. Raised ESR, anaemia and lymphocytosis are seen in majority of cases. WBC count may be high, normal or low. Occasionally metamyelocytes and nucleated RBC may be seen.
2. MANTOUX TEST: The delayed hypersensitivity skin test using purified protein derivative (PPD) is found positive in Western Countries. (Adults 40-65%, children 85-90%. But PPD lacks specificity in developing countries due to BCG vaccination and sensitization to environmental mycobacteria.
3. CSF Study: (Clear CSF with moderately raised cells and protein and low glucose is classical)
(a) Cytology: In TBM the leucocyte count is between 100-500 cells /l, rarely exceeding 1000cells /l. Lymphocyte usually predominant. In acute stage polymorphonuclear cells are usual. Occasionally cell count may be normal. Rarely CSF may be haemorrhagic due to fibrinoid necrosis of vessels. Malignant cells are not found.
(b) Biochemical:
Protein: Value ranges from 100 to 200mg/dl . In cases of spinal block it may exceed 1gm/dl and xanthochromic. If allowed to stand a pellicle or cobweb may form indicating presence of fibrinogen which is highly suggestive of TBM. Protein may be normal in some cases of AIDS and TBM.
Glucose: In majority cases less than 40% of corresponding blood sugar level, with a median value between 18 t0 45 mg/dl. Unlike pyogenic meningitis it is never undetectable level.
Chloride: Low chloride level is a non-specific marker reflecting coexisting hypochloraemia. It is unhelpful in discriminating TBM, Bacterial and viral meningitis.
(c) Microbiological Test:
A negative Gram stain, India inkstain and sterile culture for bacteria and fungi are usual. Demonstration of acid fast bacilli (AFB) in the smear and culture usually confirmatory. The number of bacteria must be more than 104/ml to detect in smear or culture. The smear is stained by Ziehl – Neelsen and auramine (positive in 4-40%). Centrifuging CSF (10-20 ml for 30 minutes) and thick smear from pellicle and repeated CSF smear enhance detection rate.

CSF culture in Lowenstein-Jensen (LJ) media takes 4-8 weeks due to slow growth. Positivity ranges from 25-75% and Indian reports mostly less than 19%. The yield can be enhanced by using liquid culture media like Septic-Chek AFB system and Middle brook 7H9. Isolation rate is higher from cisternal and ventricular CSF than lumbar. In milliary tuberculosis sputum and bone marrow may be positive.

4. Radiological Study:
A. Chest X-ray: Finding consistent with pulmonary tuberculosis is seen in 25 to 50% of case TBM in adult and 50-90% in children.
B. Skull X-ray: Acute TBM does not show any change. In hydrocephalus signs of raised intracranial pressure are seen. Flecks of calcification are seen along basal cistern or course of major vessels. Obliterative endarteritis leading to collateral channels results in enlarged vascular grooves.
C. Neuroimaging: (CT or MRI, Angiography): Reveal thickening and enhancement of meninges (60%) due to exudates seen at basal cisterns, supracellar cistern and Sylvian fissure. The exudates may be mild, moderate and severe. Hydrocephalus is seen 50-80% cases, the degree correlate with duration of disease. Cerebral infarction (28%) commonly in middle cerebral artery tertiary, edema (periventricular) and mass lesion like tuberculoma (10%) and tubercular abscess are seen. Vasculitis and thrombosis are seen as multiple hypodensity areas on CT. Serial CT is helpful to assess the progress and complications. Contrast enhanced MRI is superior to contrast CT to detect diffuse or focal granulomatous lesion, focal infarction and associated brainstem lesion. With effective treatment pathologic findings usually resolve but differ in patients and lesion to lesion in same patient. Eventually there may be permanent encephalomalacia , persistent of meningeal granuloma and at times calcification.
Angiography is useful only to differentiate tumor from tuberculoma by absence of “tumor vascularity”. For knowledge purpose in TBM angiography may show ventricular dilatation, narrowing of basal vessels and cerebral arteritis.

5. Immunological Methods: Due to variable and nonspecific feature of CSF in TBM a reliable rapid test is a need. In India TBM picture always confuse with partially treated pyogenic meningitis. Several tests which measure directly the components (antigen) of M. tuberculosis and indirectly the host response (antibody) have been tried. They vary in their specificity and sensitivity.
a) Antibody detection: Antibodies against variety of antigens maybe detected in CSF. They are more sensitive than specific as they are compromised by low level, circulating, cross reactive antibodies. Antibodies to soluble Mycobacteria extract earlier detected in 68% of TBM. But also showed false +ve in pyogenic meningitis probably due to previous exposure and latent infection. Recently antibodies to a variety of purified antigens including Bacilli Calmette Guerin (BCG), PPD , antigen 5 , 14kD antigen, lipoarabinomannan (LAM) have been detected by ELISA , RIA and dotimmunobinding assay. In different study the sensitivity varies from 61-90% and specificity varies from 58-100%. Antibody against M.tuberculosis antigen has a better sensitivity than PPD or BCG. Assay to detect CSF cells secreting antimycobacterial antibodies though technically demanding are less useful. One study detected cells secreting antiBCG antibodies in 96% and anti PPD antibodies in 90% of TBM.
b) Antigen Detection: There are many reports of mycobacterial antigen assay using latex agglutination, radioimmunoassay, ELISA, inhibition ELISA, immunoblotting , reverse passive hemagglutination, rabit IgG against BCG, culture filtrate antigen, antigen- 5 and immunoabsorbent affinity column-purified antigen have been used. Antigen detection has been more specific than antibody assay. The combined assay of antigen and antibody improve the accuracy.
c) Circulating Immune Complexes: From serum and CSF these complexes isolated by ELISA and studied for presence of antigen and antibody. The antigen component decline during the treatment . For formation of immune complex antigen - 5 is required. The detection may vary from 60-82%
d) Other indirect measures of host response: Adenosine deaminase an enzyme produced by T-lymphocytes is elevated in CSF of 60 –100% cases of TBM. But false +ve results are found in other meningitis. CSF lymphocyte transformation assay, detecting antiBCG secreting cells in CSF, leucocyte migration inhibition assay and T-cell immunoblotting are other tests. Bromide partition test, measuring the ratio of serum to CSF bromide after a loading dose (< 1.6 is seen in TBM) can be false +ve in other meningitis and not used now a days.
e) Biochemical detection of mycobacterial products: Tuberculostearic acid, a structural component of M.tuberculosis is detected (sensitivity 75%, specificity 96%) . But cost is a limitation for wide application. The 3-(2-ketohexyl) indoline detection is another evidence.
f) Molecular methods: Amplification of mycobacterium tuberculosis- specific DNA sequence by polymerase chain reaction (PCR) is used for rapid diagnosis . There are many methods of PCR assay of which few are simple and others cumbersome. One step amplification used as conventional method has low sensitivity. Two step nested amplification is several fold sensitive. PCR has advantage of confirmation beside AFB smear on the same day. In some studies PCR is more sensitive than culture. PCR is not affected by other infecting bacteria. However in some false –ve results may be due to treatment effect, low bacterial number, small volume of CSF, method of extracting DNA. False +ve may be due to contamination with other samples like sputum. However in different studies PCR , antibody assay or immunocomplex assay the sensitivity varies.

COMPLICATIONS
Various complications and sequelae may result depending on the stage of presentation , response to treatment, age of the patients and side effect of the drugs.
TABLE – 4
. Raised intracranial pressure , cerebral oedema, stupor
. Basal meningitis with cranial nerve palsies. (II, III, IV, VI, VII and VIII)
. Focal neurological deficit and seizure ( Mental retardation , behavioral problem, organic brain syndrome, ataxia).
. Hydrocephalus
. Tuberculoma
. Tubercular abscess
. Opticochiasmatic pachymenintitis resulting in visual loss
. Tuberculosis arterites and stroke
. Endocrine disturbances like decrease growth hormone & gonadotrophin
. Hypothalamic disorder leading to loss of control of blood pressure and body temperature, delayed or precocious sexual development.
. Diabetes insipidus
. Syndrome of in appropriate ADH secretion
. Internuclear ophthalmoplegia
. Hemichorea
. Spinal block
. Spinal arachnoiditis
. Psychological or psychiatric disturbances
. Intracranial calcification
. Syringomyelia – due to vasculities of spinal arteries with ischemic myelomalacia.


TREATMENT

Delay in starting therapy is to be minimized. Though confirmation of diagnosis by PCR or immunological method is not possible in every case in disease prevalent countries, other indirect evidences like clinical diagnosis of chronic meningitis, history of pulmonary TB, exposure to open cases, chest X-ray findings, raised ESR, positive Mantoux test, CT/MRI evidence of basal meningitis or its sequelae should raise the high suspicion of TBM. A CSF study is mandatory. Prior to initiation factors like age, coexisting hepatic or renal disease and pregnancy are to be considered.

The Following are the different situations for treatment:
1. Uncomplicated TBM: Before initiation of therapy clinical staging is required and usual drugs are 1st line antitubercular drugs. Meningeal permeability is increased by non-ionisation of drugs , small molecular weight, low protein binding, high lipid solubility. Isoniazid is non protein bound and rapidly crosses the Blood brain barrier giving > 30 times MIC (minimum inhibitory concentration). Rifampicin is highly protein bound and 20% penetrate CSF, but it reaches above MIC and equally effective in TBM. Pyrizinamide penetrate CSF excellently and recommended highly in TBM due to sterilizing property and reduction of relapse. Ethambutol penetrates in inflamed meninges only posing accurate CSFconcentration measurement. Ethionamide crosses both healthy and inflamed meninges and produce high MIC. But this drug is not used due to poor outcome. Streptomycin concentration varies with severity and meningeal inflammation and slightly above MIC level. Intrathecal route of Streptomycin though produce better CSF concentration is not used due to poor outcome.

Treatment Dose
Isoniazid - 10mg/kg Rifampicin - 10mg/kg
Pyrizinamide - 40mg/kg/day Ethambutol - 15mg/kg/day
Ethionamide - 250mg/day Streptomycin - 750mg/day

Treatment Regimen: Though many regimens are tried but four drug regimen comprising Isoniazid, Rifampicin, Ethambutol or Streptomycin and Pyrizinamide are to be followed. Ethambutol is better than Streptomycin due to better CSF penetration. This regimen is highly effective unless there is drug resistence. After 2 months Isoniazid and Rifampicin are continued. Pyridoxine (Vt B6) usually co-prescribed to avoid Isoniazid induced peripheral neuropathy.

Duration of treatment:Though longer duration of treatment lower relapse rate, the cost factor , toxicity and drug compliance are greater. Though 18-24 months was recommending in past but 6-12 month treatment is adequate. For clinical stage I, II treatment for 9-12 months and for Stage III , IV treatment for 12-18 months are adequate.

Role of Steroid: The role of corticosteroid is debatable. Different studies found that it reduces mortality in stage II, III, morbidity and complications in stage I on early administration. However the possible rational use is in complications. Indications of steroid are :-
Clinical
1. Stage II and above 2. Evidence of increased intracranial pressure
3. Focal neurological deficit due to arteritis 4. Stupor 5. Spinal block
Radiological
1. Cerebral /perilesional oedema 2. Hydrocephalus 3. Infarcts
3. Opticochiasmatic pachymeningitis

The dose is 60mg/day in adult and 1- 2.5 mg/kg/day in children. Contraindications of steroid specially associated fungal infection are to be ruled out before therapy. The duration is variable depending on clinical response. But usually tapered over 4 to 6 weeks.

Immunomodulators other than steroids: They are of historical interest. Intrathecal streptokinase, streptodornase, haparin though tried not beneficial. Intrathecal PPD was tried without much effect. Intathecal hyaluronidase though decreased intracranial pressure in some was not effective. Use of Thalidomide, the drug inhibiting tumor necrosis factor (TNF - ) in rabbits had some positive results. But due to adverse outcome it is not used.
2. Drug resistant TBM: The second line drugs are tried. Ethinoamide penetrate CSF adequately, so also Cycloserine. Newer aminoglycosides and Capreomycin have poor penetration in normal meninges. Fluroquinolones though effective in pulmonary TB they have poor penetration to CSF. Linezolid may be effective.
3. TBM associated with HIV infection: Treatment is same as without HIV infection. Zidovudine is well tolerated along with Anti TB medication. Antifungal drugs interact with Anti TB drugs reducing their efficacy.
4. Management of complications: Surgical intervention required in hydrocephalus, tuberculoma and tubercular abscess. Early drainage of hydrocephalus by ventriculoperitoneal or ventriculoartrial shunt is chosen. External ventricular drainage is required before shunt when CSF protein content or polymorphomuclar cell count is high. Patient of stage I, II have better outcome than stage III or IV after shunt. Tubercular abscess requires drainage. Early use of corticosteroid prevents other complications like arteritis, opticochiasmatic arachnoiditis and other endocrinal complications. A less surgically approach may be tried with medications like corticosteroid, furosemide, acetazolamide, intrathecal hyaluronidase, daily lumbar puncture to reduce hydrocephalus.

Monitoring therapy: Usually in TBM the CSF shows typical biochemical and cytological picture. In rest the deviation may be due to partial treatment with antibiotics and steroid. Usually after antiTB therapy the cell picture briefly become polymorphonuclear but the cell count normalize in one third in 16 months and in all cases by 3 years. In all the CSF glucose normalize after 2 months and protein level normalize within 8 months of therapy.

Clinical improvement occurs at variable period and does not correlate with CSF findings. Any clinical worsening needs neuroimaging to exclude complications. Vigilance maintained to detect drug induced hepatotoxicity, optic neuritis and vestibulopathy.

PROGNOSIS:

Though clinical and laboratory indices are variable some poor prognostic indicators are – extreme age, advanced stage of the disease, concomitant extramenigeal TB and evidence of raised intracranial pressure.

CONCLUSION:

Uncertainty and doubt dominate all aspects of TBM. The variable natural history and clinical features hinders diagnosis. Z.N. staining lacks sensitivity and culture results are often time consuming for clinical judgment. New rapid diagnostic tests are incompletely evaluated and not suitable for developing countries. The duration of chemotherapy of TBM is unclear and benefits of adjuvant corticosteroid remain doubtful. The only uncomfortable certainties lie in the fatal outcome of missed diagnosis and delayed treatment.

SUMMARY:

TBM is commonest form of extrapulmonary neurotuberculosis in developing, industrialized nations. The basic pathology is subependymal (RICH FOCUS) which later on reactivated leading to intracranial structure involvement producing meningitis, vasculitis, ependymitis, encephalitis and hydrocephalus. The clinical picture is variable and neurologically classified to 4 stages. HIV infection increases more risk. TBM is to be differentiated from other conditions keeping in mind various supportive criteria’s. Though routine tests are not specific but +ve mantoux test and classical CSF findings are helpful. Radiodiagnosis like CT/MRI are helpful to evaluate complications. Demonstration of AFB in smear or culture of CSF is confirmatory but time consuming. Immunological methods though rapid but vary in specificity and sensitivity. But PCR is most sensitive. Delay in treatment leads to complications. The treatment regimen is like pulmonary TB but differ in duration of treatment depending on clinical stage. Though role of corticosteroid in debatable its early use prevents complications. In drug resistant cases 2nd line AntiTB drugs are to be given. Surgical intervention is required in hydrocephalus, tuberculoma and abscess. If TBM is not treated prognosis is fatal.


CLINICAL FOCUS

. TBM is commonest manifestation of neurotuberculosis in children in developing countries.
. The pathological process involves various intracranial tissues leading to multifarious clinical presentation.
. For treatment and prognosis TBM is classified into 4 stages.
. It is to be differentiated from other conditions of meningitis.
. Complications and sequelae may result depending on stage, age and initiation of proper therapy.
. Though diagnosis is based on clinical, various methods are used to confirm diagnosis of which CSF study and demonstration of AFB is confirmatory.
. Various immunological methods adopted for diagnosis differ in specificity and sensitivity with various limitation factors.
. The treatment regimen is like pulmonary TB but differ in duration depending on stage of the disease.
. Role of steroid though debatable has beneficial effect .
. Co-infection with HIV does not change the clinical manifestations and outcome of TBM.
. Early diagnosis and treatment results in better outcomes and less permanent sequelae.
. However many aspects of TBM like genetic, ethnic constitution and other factors effecting resistance, early , low cost high sensitivity diagnostic method are under trial.


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Jul22
DENGUE FEVER
DENGUE FEVER
INTRODUCTION:
Dengue fever (DF) is an acute febrile viral infection presenting with intense headache, bone ache, rash, leucopenia. Dengue haemorrhagic fever (DHF) is associated with pneumonia and circulatory failure leading to Dengue Shock Syndrome (DSS). Currently it poses a threat to 2.5 billion people in over 100 tropical and subtropical areas of World. International travel, new serotype to susceptible populations are a threat. Proper epidemiological and laboratory surveillance is needed to further control, prevent and treat the cases.
Dengue is a Spanish phrase “Ke denga Pepo” meaning “Cramp like seizure caused by evil spirit” during Carribean out break in 1827-1828. Worldwide incidence is 100 million. In India outbreak occurred in 1993, 1996, 2003 and 2006. In recent outbreak there were 167 death out of which at Delhi there was 61.
THE VIRUS
Belongs to family Flaviviridae (Genus – Flavivirus, species – Dengue) having 4 sero subtypes (DEN-1,2,3,4) distinguished by serological method. The virus has a single standard RNA genome surrounded by icosahedral nucleocapsid and covered by lipid envelope. The virion is about 50nm diameter. The genome is about 11 kilobases in length, the genome sequence of all 4 types are known. The genome is composed of 3 protein genes core (C), membrane associated (M) and envelope (E) and seven nonstructural protein genes. Infection by one serotype produces lifelong immunity against same serotype by partial or temporary immunity against other serotypes.
VECTORS:
The mosquito Ae aegypti found around the globe in tropical and subtropical region usually between latitude 350N and 350S and altitude of 100meters. The mosquitoes invade in warm season and die in winter. Because of its high anthropophilic nature and close proximity to human and indoor efficient vector for arbovirus. Its eggs can withstand long period of desiccation even more than a year.
Other Aedes mosquitoes for dengue are Ae albopictus, Ae polynesiensis, several species of Ae scutillaris complex.
The mosquito is known as Tiger mosquito as it has white strips on black body. It is a fearless biter. The biting hour is 2 hour after sunrise and few hours before sunset. It can fly upto 10 meters. The mosquito breads on artificial accumulation of water like discarded tin, flower pot, cocoanut shell, earthen pots, cooler water etc.,
HOST
All 4 serotypes infect human. At different settings DEN-2, DEN-3 and DEN-4 has been responsible for epidemics. The acute phase of infection following an incubation of 3-14 days lasts about 5-7 days and followed by immune response. Usually high viraemia in human leads to greater percentage of infection to feeding mosquitoes.
PREDISPOSING FACTORS:
. The commonest age group is below 12 years.
. Females suffer more than male
. Race – Caucasian> Black
. Nutritional status – Poor nutritional status is protective.
TRANSMISSION:
Once infected the Ae aegypti mosquito remain infected lifelong and transmit to human during probing and feeding. Infected female mosquito transmits to next generation by transovarian transmission. Though human is the commonest amplifying host, monkeys at some places may be the host. The virus circulates during fever and viraemia. The virus develops in the biting mosquito for 8-10 days before infecting a healthy human. This extrinsic incubation period depends on environmental factors.
PATHOGENESIS OF DHF/DSS
The two main pathophysiological changes in DHF/DSS are:
. Increased vascular permeability giving rise to plasma loss, haemoconcentration, low pulse pressure and signs of shock.
. Disorder of haemostasis involving vascular changes, thrombocytopenia coagulopathy.
Activation of complement system with decrease of C3 and C5 levels are seen. Mediators of vascular permeability and bleeding phenomena are not clear. Platelet defects are quantitative and qualitative. There is enhanced viral replication in macrophages by heterotype antibodies. The secondary infection by a different serotype , cross reactive antibodies may increase the number of infected monocytes as dengue virus antibody complexes are taken into these cells. This results in increase of CD4+ and CD8+ cytotoxic antibodies. Activation of T cells releases cytokines rapidly. Lysis of infected monocytes mediated by cytotoxic lymphocytes result in plsma leakage and haemorrhage.
Sequence of infection:
. Serotype 1 Serotype 2 more dangerous
. Serotype 4 Serotype 3 Less dangerous
. Serotype 2  Most dangerous.
PATHOLOGY OF DHF
In autopsy it has been found in order of incidence - skin and S.C. tissues, G.I mucosa, heart , liver. Subarchnoid and cerebral haemorrhage are rare.
Serous effusion (exudative) seen in pleura, peritoneum, rarely in pericardium. The capillaries and venules of involved organs show perivascular bleeding , monocyte and lymphocyte infiltration, intravascular clot.

In liver there occurs focal necrosis of hepatic cells , swelling , councilman bodies hyaline necrosis of Kupffer cells. Mononuclear proliferation occurs commonly in sinusoids and rarely in portal areas.
In autopsy viral antigen commonly seen in liver, spleen, thymus, lymphnode, lung cells. Virus has been isolated from bone marrow, brain, heart, kidney, liver, lung, lymphnode, GIT.
In nonfatal DHF the bone marrow shows depression of all haemopoitic cells which improve after fever subsides. Kidney shows mild immune complex type glomerulonephuits which resolve after 3 weeks without any residue. Biopsy of skin rash shows perivascular oedema of the terminal microvasculature of dermal papillae with infiltration of lymphocytes and monocytes. Phagocytes bearing antigen have been found in this area. Deposition of serum complement, immunoglobulin and fibrinogen on vessels has been detected.
CLINICAL PRESENTATION
Dengue infection may present as asymptomatic, undifferentiated fever, DF, DHF and DSS.
I. Dengue fever:
. The clinical features depends on age. Infants and young children have febrile illness with maculopapular rashes.
. Older children and adult may have mild febrile syndrome or classical disease by high fever of abrupt onset sometimes with 2 peaks (sadodle backed) severe headache, pain behind eyes, muscle, bone , joint pain (break bone fever), nausea, vomiting, rash. Petechial skin lesions are common. Leucopenia and thrombocytopenia is common. Recovery is associated with fatigue and depression. In some epidemics may have bleeding complications like epistaxis, gum bleeding, GI bleeding , haematuria, monorrhagia.
. The case fatality is < 1%.
. Haemorrhage in DF is to be differentiated from DHF where there is haemoconcentration.
. DF is to be differentiated from Chikungunya fever a similar vector borne viral disease with similar epidemiology and overlapping distribution.
II. Dengue Haemorrhagic fever (DHF)
. The 4 typical manifestations are high fever, haemorrhagic phenomena, hepatomegaly and circulatory failure.
. Moderate to marked thrombocytopenia with haemoconcentration distinguish it form DF. So also plasma leakage giving rise to serous effusion and hypoproteinemia.
. Commonly sudden high fever accompanied by facial flush and various nonspecific symptoms and signs may occur like anorexia, nausea, vomiting, constipation, diarrhoea, abdominal pain, infected pharynx, rhinitis , maculopapular rash, myalgia, arthralgia, enanthema, abnormal reflex, palpable spleen, febrile convulsion (children) coma.
. Common haemorrhagic phenomenon is a positive tourniquet test, easy brushing and bleeding from venepuncture site. Discrete fine petechiae over extremities, axillae, face , soft palate are seen during febrile period. Epistaxis, gingival bleeding are infrequent and GI bleeding may occur during fever.
. Liver is palpable in early febrile phase and varies in size but does not correlate with severity though hepatomegaly is more in shock syndrome. Liver is tender without jaundice. Splenomegaly is common in infants.
. The course – In severe cases after 2-7 days of fever, rapid fall of temperature, circulatory disturbances. In less severe cases mild symptoms reflect less plasma leakage. Many patients recover spontaneously after fluid and electrolyte correction. In severe cases patient may go to shock and death.
. DHF can be graded as per severity of symptoms and signs
Grade – I: Fever , nonspecific constitutional symptoms. Only haemorrhagic sign is +ve , Tourniquet test and /or easy brushing.
Grade – II: Grade I symptoms with spontaneous bleeding manifestation of skin and other sites.
Grade – III: Circulatory failure in form of rapid, thready pulse , hypotension, cold , clammy skin and restlessness.
Grade – IV: Profound shock with undetectable pulse and BP.
. During convalescence from DHF sinus bradycardia, arrythmia, confluent petechial rash with small round normal skin are seen. Maculopapular rash are less common in DHF than DF. The course of DHF is usually 7-10 days.
III. Dengue shock syndrome (DSS)
Sudden deterioration of patient after 2-7 days of febrile illness when sudden fall of temperature with signs of circulatory failure like cold, clammy skin, circumoral cyanosis, rapid, thready pulse and low pulse pressure, hypotension. Initially lethargic later may be restless. Acute abdominal pain may proceed shock. If not timely treated patient passes to profound shock stage with imperceptible BP and pulse. But consciousness is intact throughout. The duration of shock is short. The patient dies within 12 – 24 hours or recovers following volume replacement. Pleural effusion and ascites may be detected clinically or radiologically.
Uncorrected shock can give rise to complications like metabolic acidosis, severe bleeding from GIT and other organs with poor prognosis. Convulsion may occur in intracranial haemorrhage and may be comatose. Encephalopathy may occur due to metabolic, electrolyte disturbance and intracranial bleeding.
Convalescence in corrected DSS is short and uneventful. Reviving from shock patient recovers within 2-3 days with adequate urination and appetite. Ascites and pleural effusion may recover later.
COMPLICATION AND UNUSUAL MANIFESTATIONS
The unusual manifestations like CNS involvement giving rise to convulsion, spasticity, altered sensorium , transient paresis. Febrile convulsion may occur in children. Encephalopathy may be due to hypotonic solution replacement or DIC. Intracranial bleeding and brainstem herniation due to cerebral edema may occur.
Some iatrogenic complications like sepsis, pneumonia, wound infection and overhydration may occur.
Liver failure may occur in serotype1, 2, 3 with both primary and secondary infection. Hepatic necrosis with detectable dengue antigen in hepatocytes. The cause of liver damage is not known. Renal failure is a terminal event.
Other unusual manifestations are acute renal failure, haemolytic uraemic syndrome (in cases of haemoglobinopathy and G6PD deficiency). Simultaneous infections like leptospirosis , Hepatitis B, typhoid fever, chicken pox, melioidosis contribute to unusual manifestations.
LABORATORY DIAGNOSIS
1. Thrombocytopenia and haemoconcentration is a constant finding of DHF.
A. Platelet count < 100000/mm3 found between 3-8th day, often along with or before changes in Haematocrit.
B. A rise in Haematocrit is always present more so in shock. A rise of 20% or more is definite evidence of increased vascular permeability and plasma leakage.
C. A relation of drop in platelet and rise in Haematocrit is unique of DHF and occur before defervescence and onset of shock.
D. The WBC count is variable at onset ranging from leucopenia to mild leucocytosis but leucopenia with fall of neutrophil is common at the end of febrile illness. Ralative lymphocytosis with atypical lymphocytes is common before shock.
E. A transient mild albuminuria with +ve occult blood in stool is seen.
F. Coagulation profiles may show reduced fibrinogen, prothrombin, factor VIII, IX and antithrombobin III.
G. Reduced  antiplasmin seen in some cases, serum albumin reduced.
H. In severe liver dysfunction reduced level of Vit K dependent factors like factor V, VII, IX, X are seen. Prothrombin time and partial thromboplstin time is prolonged in 30-50% cases of DHF. Thrombin time is prolonged in severe cases. BT and CT are prolonged..
I. Platelet function is impaired and reduction of complement specially C3 is seen.
J. Other common findings are – Hypoproteinaemia, hyponatraemia and raised serum asparate aminotransferase. In shock there is metabolic acidosis with raised blood urea nitrogen.
K. X-ray chest may show pleural effusion (right side). In shock there is bilateral pleural effusion.
2.Virus and serological test
L. Isolation and detection of virus – Since all patients have a period of viraemia, the virus can be isolated in the course of the disease.
Detection of dengue virus by culture is definitive diagnostic test though practically it has many limitations. As antibody develops within days and the virus being heat labile collection and transport of specimen need care. Detection of dengue RNA using specific oligonucleotide primers, reverse transcriptase and thermostable polymerase – a test known as reverse transcription polymerase chain reaction (PCR) amplification assay is useful. The plasma , serum or cell can be used for this. Determination of virus and antibody type is preferable. Inoculation of clinical specimen to adult or larval mosquito is used for virus culture.
M. MAC ELISA Test: In primary and secondary dengue infection ELISA can measure the rise of specific IgM collected in the acute phase. Four fold rise of Ig G and IgM antibody is diagnostic.
N. Haemagglutination inhibition (HI test) – useful for diagnosis.
O. Neutralization Test: Most sensitive and specific test is serum dilution, virus constant, plaque reduction test. Following primary infection specific neutralizing antibody is seen in early convalescence. Following secondary infection high titre neutralizing antibody is produced against at least 2 or all 4 serotypes.
P. Dot bolt immuno assay: Now technique under consideration.
Q. Complement Fixation Test (CFT) : Though less sensitive it appears later than IgM or HI antibody but more specific . Useful for confirmation in later period. A 4 fold rise of CFT antibody where the interval between acute and convalescent is < 2 weeks signifies secondary seroresponse pattern.
R. Dengue virus antigen is autopy tissues may also be detected by immunohistochmistry, immunofluroscence.
DIFFERENTIAL DIAGNOSIS
In the early febrile phase DHF/DSS a wide spectrum of viral, bacterial, parasitic infections are to be taken into consideration. Chikungunya fever is difficult to differentiate from dengue clinically. But by 3-4 days the laboratory findings will establish dengue. Shock never occurs in Chikungunya. Thrombocytopenia and haemoconcentration excludes endotoxic shock.
Chikengunya fever (compared to DF)Duration of fever - < 7days
Haemorrhage - Less
Gn bleedig - 0
Haematemesis /Melana - 0
Shock - 0
Coma - 0
Abnormal reflux - 0
Hepatomegaly/palyarthralgia - more
TREATMENT
. The major pathological abnormality in DHF/DSS is increased vascular permeability leading to loss of plasma volume. The major haemostatic changes in DHF are vascular changes (due to short acting mediators), thrombocytopenia and disorder of coagulation which leads to DIC and haemorrhagic complications.
. Early and effective replacement of plasma by plasma expander or fluid and electrolyte correction leads to favourable outcome even DSS may be reversible. Resuscitation from shock, correction of acidosis have good prognosis.
. Repeated Haematocrit and platelet count during illness is essential to assess signs of deterioration.
. DHF – Oral hydration with electrolyte is encouraged. Antipyretics are to be avoided to prevent acidosis, bleeding and Reye and Reye like syndrome. Paracetamol is preferable. Parenteral IV fluid is indicated if vomiting or hypotension. Bicarbonate containing IV fluids should be avoided initially. Vital signs, urine output are to be monitored.
. Calculation of maintenance of IV fluid
Body Weight Maintain volume (ml) over 24 hours
10 Kg 100/kg
10-20 Kg 1000+50 for each kg in excess of 10
>20 Kg 1500+20 for each kg in excess of 20
Total fluid required = +10ml /1% normal body weight loss

. DSS
It is a medical emergency. Immediate IV fluid or plasma expander are given. Hyponatremia and metabolic acidosis are to be corrected. Sedatives may be indicated if patients is restless. Avoid hepatotoxic and long acting drugs. A single dose of chloral hydrate (12.5 –15mg /kg) orally is preferable. Oxygen therapy is given if needed. Blood transfusion – indicated when there is internal haemorrhage. Fresh whole blood is preferable. Fresh frozen plasma or concentrated platelets indicated is coagulopathy
. To be given or done - Rest, Fluid/Electrolyte and Acetaminophen.
. Not to be done or given - Aspirin, Brufen, IV therapy before haemorrhage, Blood transfusion, Antibiotic, No injection and No steroid.
PREVENTION AND CONTROL
. Killing of adult mosquitoes by space spray. Theramal fog (insecticide +oil), ULV aerosal (cold fog) and mist. Insecticide used as – Malathion, Fenitrothion, Fenthion, Pyrethroids
. Control of mosquito bite: using repellant oil, use of full clothing, mosquito net
. Eliminate breeding site: Spray larvicides like Temephos sandgranules and insect growth regulator Methoprine in form of brequets.
. Biological control by using Bacillus thurigienisis – H-14 BTI.
. No vaccine yet available.
. Health education,environmental sanitation is best way for prevention.
SUMMARY:
Dengue fever is one of the commonest arthropod borne viral haemorrhagic fever found in tropical or subtropical countries worldwide. The vector has close proximity to human. The virus has 4 serotypes out of which serotype 2 is dangerous. Dengue fever may lead to DHF or DSS depending on the serotype, adequate early treatment and host response. Dengue fever may simulate other fevers specially Chikungunya fever. The pathophysiology of DHF and DSS is increased vascular permeability, haemoconcentration and disorder of haemostasis including thrombocytopenia. The diagnosis depends on clinical symptoms and signs with laboratory findings and commonly thrombocytopenia, rise in haemotocrit value. Virus can be detected on culture. Different serological test are helpful to establish the diagnosis. The treatment is symptomatic with special emphasis in maintaining fluid and electrolyte balance. The measures to eradicate the vector is best prevention.
CONCLUSION:
In tropical and subtropical countries the menance of Dengue is a constant feature. Epidemics occur very often with high morbidity and mortality . Early proper diagnosis, adequate management of DHF and DSS decreases the mortality. Control of mosquitoes and environmental sanitation is best way to prevent the disease.


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Jul22
ANTIPHOSPOLIPID ANTIBODY SYNDROME
ANTIPHOSPOLIPID ANTIBODY SYNDROME

INTRODUCTION:-
Antiphospholipid Syndrome (APS , APLS), also known as Antiphospholipid antibody syndrome or ‘Sticky blood Syndrome’or Hughes syndrome is a disorder characterized by elevated level of multiple different antibodies that are associated with arterial and venous thrombosis and pregnancy related complications. This syndrome occurs due to auto antibodies against phospholipids (aPL), a cell membrane substances. The antibodies are found against cardiolipin (anticardiolipin antibodies) and β2 glycoprotein I (β2 GP1).
These aPL antibodies were first seen in some patients with positive test for syphilis without infection out of which few developed SLE(Systemic Lupus Erythematosus ) and other similar conditions. Later lupus anticoagulant was detected in few cases of SLE. A case report in 1956 showed repeated pregnancy loss,thrombophlebitis and lupus anticoagulant. In 1980 the rheumatologist Dr. Graham R. V. Hughes of St. Thomas’ Hospital , London provided the details including the test for anticardiolipin antibodies. Later anticardiolipin antibodies were found to act against β2GP1,while lupus anticoagulant was found to act against β2GP1 and more recently prothrombin.
CLASSIFICATION:-
It can be classified as
1. Primary - without any related disease.
2. Secondary – in conjunction with autoimmune diseases like SLE .
3. Catastrophic APS (CAPS) – Rapid multi organ failure due to thrombosis leading to death.
AETIOLOGY:-
Normal person may have antibodies. The triggering factors are:-
1. Infections- People with Syphilis ,HIV infection, Hepatitis C, Malaria.
2. Medications- Antihypertensive like hydralazine , antiepileptic like phenytoin, antibiotics like amoxicillin. Cocaine, procainamide, quinine may cause.
3. Genetics – Although APS has been reported to occur in multiple members of the same family, no clear inheritance pattern has been identified and no gene has been found to be the sole cause of this condition. One report in 1999 studied families with more than one affected member, examined possible modes of inheritance, and examined links with certain genes. In seven families 30 out of 101 family members met diagnostic criteria for the syndrome. The data were fitted best by either a dominant or co dominant models.
PATHOGENESIS:-
Antiphospholipid syndrome is an autoimmune disease in which “antiphospholipid antibodies”(Anticardiolipin antibodies and Lupus anticoagulant) react against protein that bind to anionic phospholipids on plasma membranes. Like many autoimmune diseases , it is more common in women than in men. The exact cause is not known, but activation of the system of coagulation is evident. Clinically important antiphospholipid antibodies are associated with thrombosis and vascular disease.
Anti-ApoH and a subset of Anti-cardiolipin antibodies bind to ApoH , which in turns inhibits Protein C, a glycoprotein with regulatory function upon the common pathway of coagulation(by degrading [Va factor]).
LAC antibodies bind to prothrombin, thus increasing its cleavage in thrombin, its active forms.
In APS there are also antibodies binding to Protein S, which is a co-factor of protein C. Thus Anti-Protein S antibodies decrease Protein C efficiency.
Annexin A5, which forms a shield around negativity-charged phospholipids molecules, thus reducing their availability for coagulation. Thus Anti-annexin A5 antibodies increase phospholipids-dependent coagulation steps.
The Lupus anticoagulant antibodies are those that show the closest association with thrombosis, those that target β2GP1 have a greater association with thrombosis than those that target prothrombin. Anticardiolipin antibodies are associated with thrombosis at moderate to higher titres (> 40 GPLU or MPLU). Patients with both Lupus anticoagulation antibodies and moderate/high titer anticardiolipin antibodies show a greater risk of thrombosis than with one alone.
INCIDENCE:-
The aPL antibodies are found in 30% cases of SLE. The aPL antibodies may be found in 1-5% of normal individuals. There is no racial predisposition of Primary type. It is more common in young adults(30-45 yrs). Primary APS accounts for over 50% cases. Some studies indicate that aPL antibodies may play a role in approximately one third of strokes in persons under age of 50.A female predominance causing secondary APS parallels APS with SLE and other connective tissue disease .After age of 60 incidence is rare.
CLINICAL FEATURES:-
APS usually shows up for the first time as vascular thrombosis or embolism or as recurrent pregnancy loss. Thrombocytopenia , certain skin problems, neurological signs, heart valve disease and certain autoimmune diseases have also have been noted in association with APS. Pulmonary hypertension and sensory- neural hearing loss have been noted in some individuals with APS as well.
Conditions associated with APS include:
1. Systemic Vascular Thrombosis
While the deep veins of the legs are most frequent sites of thrombosis, thromboemblism can involve virtually any vein or artery. Deep vein thrombosis tends to be most common finding, occurring in half of affected individuals. Other sites of venous thrombotic events include the veins of the lungs (due to pulmonary embolism, a clot that typically has dislodged from a vein below the pulmonary veins and lodged in a pulmonary veins), thoracic veins(veins in or above the chest that carry blood to the heart including the superior vena cava, or jugular vein), and abdominal or pelvic veins.
A risk of recurrent thrombi is associated with APS as well. Most studies suggest that individuals who have a recurrent episode will have it in a similar blood vessel type. For example, indivisuals who have a stroke initially will most often have a stroke if they have a recurrence. Nonetheless, individuals are reported who have had different types of thrombosis events.
A deep vein thrombosis( DVT) can form in the arm or leg after a long journey, or in some women, after starting the contraceptive pill. Clots in the veins can cause thrombophlebitis of the legs with pain in the thigh or calf, swelling of the leg , and sometimes a visible red, thickening blood vessel. Damage to the valves of lower limbs may impair the upward venous flow leading to chronic venous insufficiency causing chronic swelling and discoloration of leg. Thrombosis can also affect vital organs such as the eye, liver and kidney.

2. Pregnancy Loss and Other Complications
APS is associated with miscarriages as well as other complications of pregnancy. Most studies have estimated the prevalence of aPL antibodies among pregnant women at 5 percent or less, most of these women do not have any signs or symptoms of APS. Around 10-20 percent of women with multiple pregnancy loses are thought to have APS.
Women with APS often have a history of recurrent (usually defined as three or more) pregnancy losses. Pregnancies occurring in women with APS are at increased risk of prematurity , slower than expected growth of the fetus, and preeclampsia. Pregnant women with APS are also more prone to develop deep vein thrombosis during pregnancy or puerperium .
One miscarriage is a disaster. Two is worse. Imagine the suffering of women who have 3,5,7 or even 12 pregnancy losses, and sometimes as late as the late few weeks of their pregnancy.
We now know that Hughes Syndrome is the most common treatable cause of recurrent miscarriage. Future more, late pregnancy loss, fortunately an unusual problem in pregnancy, is very strongly associated with Hughes Syndrome as is pre-eclampsia, placental abruption and intra-uterine growth restriction.
For the sake of a simple blood test, patients with miscarriage or late pregnancy loss can be tested for Hughes Syndrome. Treatment of these patients has proved one of the true success of modern medicine , the successful pregnancy rate rising from a previous low of fewer than 20% to figures now in the region of 75-80% success rate.
3. Thrombocytopenia
An association with immune thrombocytopenia has been established. This occurs to varying degrees in many as 50% of individuals with APS. Because platelets help the blood to clot, thrombocytopenia can sometimes cause a bleeding disorder in an otherwise healthy person as bleeding from gum, nose and skin. However in APS thrombocytopenia is usually moderate and is rarely significantly enough to cause bleeding complications or affect anticoagulant therapy.
4. Skin Disorders
Certain skin conditions have also been observed in APS. These include livedo reticularis (mottled discolouration of the skin), ulcers on the skin, usually on the legs, and sometimes skin necrosis .
Many Hughes Syndrome patients complain of ‘cold circulation’ and this sometimes manifest as a blotchy appearance of the skin of the arms and legs, described in medical textbooks as “livedo reticularis” or “corned beef skin”. It can also cause repeated sores and bumps (nodules) of the skin.
5. Stroke and Other Neurological Disorder
Stroke is associated with APS as are some other neurological conditions. In addition to cerebrovascular thrombosis , embolic stroke can also occur. Multiple strokes can sometimes leads to a condition called multi-infarct dementia.
Other neurological problems have been reported in people with aPL antibodies, although they are not as strongly associated with APS as stroke. These include seizures, chorea , migraines, Guillain-Barre syndrome, diabetic peripheral neurotherapy, transverse myelitis and conditions similar to multiple sclerosis. Evidence for an association with cognitive dysfunction is growing.
There are many cause of strokes- for instance hypertension but most surveys show that 1 in 5 young strokes (under the age of 45) are now associated with Hughes Syndrome(APS). Now, in the age of easy diagnoses of Hughes Syndrome, many patients are not receiving adequate anti-coagulant treatment of their “sticky blood” , and suffering from early mini-strokes or TIAs (transient ischemic attacks) or more permanent strokes.
Some people with Hughes Syndrome develop a syndrome which is very similar to multiple sclerosis where they have numbness or pins and needles, double vision or loss of part of the field of vision, and have difficulty in walking. Consequently one of the main alternative diagnosis in patients with Hughes syndrome is multiple sclerosis.
6. Heart Disease
A type of heart valve disease called Libman-Sacks endocarditic is sometimes seen in individuals with aPL antibodies. In this condition, growth on the heart can break off and travel through the blood streams, causing embolic events. Hughes Syndrome can lead to heart attacks and heart valve problems that can mimic bacterial endocarditic, and create clots in the upper chambers of the heart. Up to20% of young people (under 45) who have a heart attack have antiphospholipid antibodies.
7. Lupus and Other Autoimmune Disorder
APS is classified within the category of autoimmune disorders . Individuals with aPL antibodies sometimes have an additional autoimmune disorder, most commonly SLE. About 30-40 percent of individuals with SLE have elevated aPL antibodies. APS has also been associated with a number of other autoimmune disorders, including myasthenia gravis, Graves’ disease, autoimmune hemolytic anemia and Evan’s syndrome.
8. Headache or migraine
Often this is one of the major features of the illness. Sometimes the headaches disappear in the 20’s to return with a vengeance in the 30’s or 40’s. This is a most important feature of Hughes Syndrome and symptoms sometimes improve dramatically when treatment is started. Often migraine features such as flashing lights and zigzag patterns accompany the headaches found in Hughes Syndrome.
9. Giddiness
For reasons not completely understood the brain appears particularly sensitive to the clotting effects of antiphospholipid antibodies and one of the ways in which it reacts to “Sticky blood” affecting its oxygen supply is to cause balance disorders. Many patients complain of feeling giddy or “slightly drunk” and this can naturally lead to accidents.
10. Memory loss
When the brain is starved of oxygen it only has a limited number of ways of complaining and a common symptoms of Hughes Syndrome is memory loss. Many patients feel that they are developing Alzheimer’s disease when they can’t remember names of friends and family , forget their shopping lists and get their word and sentences muddled. One of the most dramatic observations is the improvement of the memory (and the disappearance of the headaches and ‘fog’) which patients observe when blood thinning medicine is started.
11. Visual disturbance
In addition to the flashing lights and zigzag patterns which can accompany headaches and migraines, the person with Hughes Syndrome can experience double vision or sudden visual loss. This can be caused by the brain reacting to disturbances in its supply of blood or by the veins and arteries in the eye being affected.
12. Pulmonary embolism
A pulmonary embolism occurs when a blood vessel supplying the lung becomes clogged up by a clot. Blood clots in the lung can cause chest pain, shortness of breath and rapid breathing. Repeated clots can cause pulmonary hypertension which may cause the person to be constantly short of breath. Larger emboli in the lungs can be lethal.
13. Gastrointestinal disorder
Hughes Syndrome can affect the blood supply to the intestine causing abdominal pain, fever and blood in the stool. Antiphospholipid antibodies can also cause a condition called Budd-Chiari syndrome, in which a blood clot prevents blood from flowing out of the liver and the person may then experience nausea, vomiting, jaundice, dark urine and the swelling of the abdomen.

DIAGNOSIS:-
Diagnosed on the basis of clinical and laboratory findings. History of episode of thrombosis and pregnancy loss is important.
Laboratory Test- APS is diagnosed if an individual experiences one or more episodes of thrombosis or pregnancy loss and if aPL antibodies are detected through laboratory testing of the individual’s blood.
There are two main types of antiphospholipid antibody tests- immunological tests, like the anticardiolipin ELISA (enzyme-linked immunoassay), and coagulation-based tests for the lupus anticoagulant. ELISA are immunologically based tests, or immunoassays in which an antigen-antibody reaction is used to detect the antibodies. In contrast, lupus anticoagulant tests detect antibodies based on their ability to slow down phospholipids-dependent clotting reactions. Most individuals with APS have antibodies that can be detected in both tests. However a significant percentage of patients are positive in one test but not the other. Therefore to diagnose APS it is standard practice for both tests to be performed. The tests are then repeated six to eight weeks later to confirm the presence of aPL antibodies.
Antiphospholipid syndrome is tested in the laboratory using both liquid phase coagulation assays(lupus anticoagulant) and solid phase ELISA assays (anti-cardiolipin antibodies).
Genetic thrombophilia is part of the differential diagnosis of APS and can coexist in some APS patients. Thus genetic thrombophilia screening can consists of :
• Future studies for Factor V Leiden variant and the prothrombin mutations. Factor VIII levels, MTHFR mutation.
• Levels of proteins C , free and total protein S, Factor VIII, antithrombin , plasminogen, activator(TPA) and plasminogen activator inhibitor-1(PAI-1)
The testing of antibodies to the possible individuals targets of aPL such as β2 GP1 and antiphosphatidyl serine is currently under debate as testing for anticardiolipin appears to be currently sensitive and specific for diagnosis of APS even though cardiolipin is not considered an in vivo target for antiphospholipid antibodies.
Lupus anticoagulant
This is tested for by using a minimum of two coagulation tests that are phospholipid sensitive, due to the heterogeneous nature of the lupus anticoagulant antibodies. The patient on initial screening will typically have been found to have a prolonged APTT that does not correct in an 80:20 mixture with normal human plasma(50:50 mixes with normal plasma are insensitive to all but the highest antibody levels). The APTT (plus 80:20 mix) , dilute Russell’s viper venom time(DRVVT), the kaolin clotting time (KCT), dilute thromboplastin time(TDT/DTT) or Prothrombin time(using a lupus sensitive thromboplastin) are the principal tests used for the detection of lupus anticoagulant. The tests must be carried out on a minimum of two occasions at least 6 weeks apart and be positive on each occasion demonstrating persistent positively to allow a diagnosis of antiphospholipid syndrome. This is to prevent patient with transient positive tests (due to infection etc) being diagnosed as positive.
Distinguishing a lupus antibody from a specific coagulation factor inhibitor (e.g. Factor VIII). This is normally achieved by differentiating the effects of a lupus anticoagulant on factor assays from the effects of a specific coagulation factor antibody. The lupus anticoagulant will inhibit all the contact pathways antibodies (Factor VIII, Factor IX, Factor XI and Factor XII). Lupus anticoagulant will also rarely cause a factor assay to give a result lower than 35 iudl(35%) where as a specific factor antibody will rarely give a result higher than 10iudl(10%). Monitoring IV anticoagulant therapy by the APTR is compromised due to the effects of the lupus anticoagulant and in these situations is generally best performed using a chromogenic assay based on the inhibition of factor Xa by Antithrombin in the presence of Heparin.
Anticardiolipin antibodies
These can be detected using an enzyme-linked immunosorbent assay(ELISA) immunological test which screens for the presence of β2GP1 dependent anticardiolipin antibodies(ACA).
A low platelet count and positively for antibodies against β2GP1 or phosphatidyl serine may also be observed in a positive diagnosis.
Clinical significance
Research in 2009 suggest elevated IgA anti-β2GPI antibody titers may identify additional patients who have clinical features of APS but who do not meet current diagnostic criteria, thus testing for IgA anti-β2GPI antibodies when other aPL tests are negative and APS is suspected may be in order.
The diagnosis of APS is made in case of a clinical event( vascular thrombosis or pregnancy event) and repeated positive tests of aPL performed 12 weeks apart( repeat aPL testing is necessary due to the naturally occurring presence of transient low levels of aPL following infections).
The Updated Sapporo APS Classification Criteria (1998,published in 1999)are commonly used for APS diagnosis.
Based on these criteria, APS diagnosis requires:
a).Vascular thrombosis (blood clots) in any organ or tissue or Pregnancy Event (one or more miscarriages after 10th week of gestation , three or more miscarriages before 10th week of gestation, or one more premature births before 34th week of gestation due to eclampsia) and
b).Persistency (6weeks apart) of positive aPL ( lupus anticoagulant test, moderate-to-high titer anticardiolipin antibodies or moderate-to-high titer β2GPI antibodies).


The International Consensus Statement is commonly used for Catastrophic APS diagnosis. Based on this statement CAPS diagnosis requires:

a) Vascular thrombosis in three or more organs or tissues
b) Development of manifestations simultaneously or in less than a week
c) Evidence of small vessel thrombosis in at least one organ or tissue
d) Laboratory confirmation of the presence of aPL.
Some serological tests for syphilis may be positive in aPL-positive patients (aPL bind to the lipids in the test and make it come out positive) although the more specific tests for syphilis that use recombinant antigens will be negative.
TREATMENT:-
There is no cure but medications may reduce the risk of thrombosis. Despite our increased understanding of the syndrome the cornerstone of therapy remains antiaggregant and anticoagulant agents.
• Very ill patients requires hospitalization. Usually may be treated in outdoor. A variety of specialists are required.
• Desirable to limit blood coagulation including quitting smoking, ceasing oral contraceptives, control BP.
• In cases of P/H of thrombosis long-term medication like warfarin.
• In pregnant cases need treatment and monitoring to avoid complication.
• Treatment for APS must be individualized according to the person’s current health status and the types of problems that has experienced due to their APS. In general, for a person who has aPL antibodies and had a thrombotic event a short-term course of heparin is followed by long-term( sometimes life-long) treatment with warfarin.
In women with moderate to high levels of aPL antibodies and a history of pregnancy loss who wish to get pregnant again individualized. After consulting with obstetrician and rheumatologist and /or hematologist women generally begin treatment with heparin and low-dose aspirin. For those individuals who have been found to have aPL antibodies but no signs or symptoms of APS low-dose aspirin is generally recommended. Hydroxychloroquin(HCQ) an antimalarial drug used for Lupus and Rheumatoid arthritis is under trial.
If you or someone you know has been diagnosed with APS, we recommend talking with a health care provider to determine a personalized course of management.
SUMMARY:-
APS is an autoimmune disease associated with arterial and/or venous thrombosis and pregnancy related complications. The antibodies responsible are anticardiolipin antibody, lupus anticoagulant and anti β2GP1. They may be classified as Primary, Secondary or CAPS. Various types of infection, drugs or genetic factors are thought to be triggering mechanism. It is common in young with a female prepondence. It is found in -5% of normal persons. Incidence is high in association of SLE and other autoimmune diseases. It may present as recurrent systemic vascular thrombosis and embolism, pregnancy related complication specially recurrent miscarriage, thrombocytopenia, bleeding diathesis, skin manifestation, cardiac involvement, various neurological complications, psychiatric manifestation, pulmonary and gastrointestinal, ocular, renal complication. Diagnosis depends on history, clinical examination and laboratory investigation which demonstrate aPL antibodies through ELISA (anticardiolipin antibodies) and coagulation based test for Lupus anticoagulant. Thrombocytopenia and antibody against β2GP1 may be detected. There is no cure but treatment is individualized basing on preventing risk factors and ant platelet and anticoagulant therapy.
CONCLUSION:-
APS is an incurable autoimmune disease occurring in young. Recurrent thromboembolic episodes involving various organs, recurrent abortion and other manifestations like stroke in young, pulmonary hypertension, unexplained headache, dizziness, memory impairment, cardiac involvement with embolism, dermatological involvement and other neuropsychiatric disorders brings the patient to different clinicians. Basing on proper clinical history the diagnosis is confirmed by demonstrating antibodies like anticadiolipin, lupus anticoagulant and β2GP1. Treatment is symptomatic, prevention of risk factors and individualized use of anticoagulant.
CLINICAL FOCUS:-
• APS is an autoimmune disease due to presence of aPL antibodies like anticardiolipin, lupus anticoagulant and β2GP1.
• Recurrent thromboembolism in young leading to various clinical manifestation are to be kept in mind.
• Recurrent miscarriage in young females one has to think of APS.
• Incidence is high in association of SLE and other autoimmune diseases.
• Stroke in young or myocardial infarction, renal failure and other systemic complications do occur in young.
• Thrombocytopenia may occur in 50% cases of APS with bleeding manifestations.
• Diagnosed by demonstration of antibodies through ELISA &coagulation based test.
• Though there is no cure for the illness, prevention of risk factors and use of anticoagulants depending on clinical state and symptomatic treatment is useful.


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Jul22
TUMOR MARKERS
TUMOR MARKERS

INTRODUCTION :-
Tumor markers are biochemical substances usually proteins released by tumor cells either due to cause or effect of malignant process. Some are specific while others are seen in several cancers. Many are also seen in non-cancerous conditions. They may be intracellular seen in tissues or released into circulation. Search for suitable markers in serum, tissues or body fluids during neoplastic process is of clinical value. Though an ideal marker should be highly sensitive, specific, reliable with high prognostic value and correlate with staging none of the markers identified so far has all the features. However they are helpful to monitor in risk groups, diagnose the probable source, staging the cancer, determine prognosis, guide & monitor treatment and detect recurrence.

CLASSIFICATION :- Broadly they may be classified as :-
1. Oncofetal antigens:-α-fetoprotein(AFP), carcinoembryonic antigen (CEA), pancreatic oncofetal antigen, fetal sulfoglycoprotein etc.
2. Tumor associated antigen/Cancer antigen e.g. CA-125,CA-19-9,CA 50 etc.
3. Hormones e.g. β human chorionic gonadotrophin, calcitonin, placental lactogen etc.
4. Hormone receptors e.g. estrogen & progesterone receptors.
5. Enzymes and isoenzymes e.g.-PSA(prostate specific antigen),PAP(prostatic acid phospatase),NSE(neuron specific enolase),TDT(terminal deoxy nucleotidyl transferase ),PALP(placental alkaline phospatase), lysozymes, alpha amylase etc.
6. Serum&tissueproteins-β2microglobulin,monoclonalimmunoglobulin/paraproteins, GFAP(glial fibrillary acid protein), proteinS-100, ferritin, fibrinogen degradation products etc.
7. Other biomolecules e.g. polyamines.
Some are commonly in use while others are less common.
IDEAL TUMOUR MARKER An ideal tumor marker should have---
1. Highly sensitive and less false negative.
2. Highly specific and less false positive.
3. Should have high +ve &-ve predictive value.
4. 100% accuracy in differentiating healthy & cancer patients.
5. Differentiate between neoplastic & non-neoplastic conditions showing +ve correlation with tumor volume and extent.
6. Predict early recurrence and have prognostic value.
7 . Clinically sensitive to detect in early stage.
8. Level should precede neoplastic process to screen early.
9. Should be universal to all or specific to one malignancy.
10. Easily assayable , able to indicate all changes during treatment.

DESCRIPTION:-
1.Alpha fetoprotein(AFP)— It is a major fetal serum globulin with a molecular weight of 65000. In fully matured fetus the AFP gene is completely repressed leading to its disappearance soon after birth. Though abundant in fetal blood, in normal adult the value is 15ng/ml. A value of serum AFP >500ng/ml indicate malignancy besides pregnancy. During fetal life AFP is synthesized in liver (main), yolk sac and GI tract. Fetal liver produce AFP about 30mg/day. In first trimester amniotic fluid contain yolksac derived AFP (Concanavalin-A non reactive). Later increased portion of AFP is liver derived(Concanavalin-A reactive). AFP reaches a peak between 30-32 weeks of pregnancy and decline suddenly before term. Clinical significance of AFP level is of value in prenatal diagnosis of open spina bifida, anencephaly, atresia of esophagus and multiple pregnancy.AFP level also aid in diagnosis,prognosis and monitoring primary hepatocellular carcinoma, hepatoblastoma, non seminomatous testicular germ cell tumors like embryonal carcinoma, teratoma, choriocarcinoma, yolksac carcinoma, germ cell tumors of ovary and extragonadal germ cell tumors. Most well differential and highly anaplastic hepatomas do not produce AFP, as AFP synthesis is associated with degree of liver cell differentiation. Significant rise of AFP is rarely seen in malignancy of GIT, pancreas, lungs, kidney and breast etc. Moderate rise of AFP is seen in viral hepatitis, chemical hepatic injury, hepatic necrosis, liver surgery. AFP < 400ng/ml is seen in 10-15% cases of acute and chronic hepatitis, cirrhosis, secondary malignancies. Serial AFP estimation shows steady and progressive rise in malignancies in contrast to fluctuation in nonmalignant condition. Pure seminomas are nonsecretor of AFP whereas in nonseminomatous germ cell tumors the AFP indicate progress, monitor treatment and recurrence. Dysgerminomas are AFP nonsecretors while highly malignant endodermal sinus tumours show raised AFP. Measurement of serum AFP is helpful in diagnosis, prognosis, and monitoring efficiency of chemotherapy, radiotherapy, surgery and recurrence of all malignancies discussed. Yolk sac and liver AFP synthesized during fetal and adult life are immunologically cross reactive but different. Because of their affinity to lectin AFP can be resolved to concannavalin A reactive(R con A) and non-reactive (NR con A) fraction. Quantitive as well as qualitative evaluation of AFP vaiant reveal two types, one specific to liver and other to yolk sac.

2.Human chorionic gonadotrophin(βHCG):- HCG, A marker of germ cell tumors and trophoblastic disease, is 45KD glycoprotein, composed of two dissimilar subunits the αchain(14 KD) and βchain(24 KD). It contains 30% carbohydrate. The beta subunit determines the immunological and hormone specificity. HCG is synthesized by the synctiotrophoblasts of the placenta during pregnancy. The peak HCG concentration is reached between 10th & 12th weeks of gestation. The reference values in serum of healthy men and non-pregnant women are less than 5 IU/ml and post-menopausal women are less than 10IU/ml. HCG is a marker of first choice for gonadal (testes and ovary) choriocarcioma. HCG shows 100% sensitivity for choriocarinoma irrespective of their site in addition to hydatidiform mole. In testicular tumors, the detection of βHCG and AFP correlate with the histological findings and is therefore crucial for the therapeutic procedures with the use of serial determination of βHCG. The biochemical recurrence precedes by 3 months before the patient has symptoms of clinical recurrence/metastasis. The marker also helps in monitoring high-risk group of testicular tumors especially individual with undescended testicle or the healthy monozygotic twin of a testicular tumor patient. High levels of βHCG indicate poor prognosis and frequent assays during therapy level correlate to the clinical response. Serum βHCG levels are rarely elevated in nontrophoblastic tumors such as lung, breast, pancreas and bladder cancers.

3.BETA-2Microglobulin(β2M):- β2M is 11 KD light chain constituent of HLA antigen. The β2M is used clinically as a marker of first choice for B-cell leukemia, lymphomas and multiple myeloma. However, due to its non-specificity its moderate elevation is observed in cases of solid tumors and also in various inflammatory diseases, benign infectious disorders, and primary billiary cirrhosis and in acquired immune deficiency syndrome. It is used routinely for evaluating tumor cell load, disease activity and prognosis. It is also used to monitor efficacy of patient’s response to treatment. Elevated levels of β2M are also reported in cerebrospinal fluid (CSF),in CNS metastasis, acute lymphoblastic leukemia. lymphoma and other lymphoproliferative disorders/diseases. Hence the determination of β2M in CSF helps in identifying and managing CNS metastases. Serum β2M could be clinically relevant marker for Waldenstrom’s macroglobulinemia, secretary and non-secretary multiple myeloma, leukemia and lymphoma. Like other tumor markers, β2M has proven to be the best marker for monitoring therapeutic courses, as it useful serum parameter to monitor tumor progression as well as early biochemical relapse. Serum β2M is the most powerful prognostic marker of monoclonal gammapathies.

4. BRCA 1 &BRCA 2:- BRCA 1and BRCA 2 belong to few tumor suppressor susceptibility genes having high risk to few cancers.BRCA1 predicts high risk for breast, ovary, colon and prostate cancers. BRCA2 gene mutation is seen in 70% of breast cancers in women and men. More than 100 germ line mutations are reported in BRCA gene applying current molecular technology.

5.BTA(Bladder tumor antigen):- Not widely used. Urine level helps in diagnosis and recurrence of bladder tumors. May be raised in kidney stones and urinary tract infection.

6.Carcino-embryonic antigen(CEA): -CEA, is a glycoprotein of 200 KD. Radioimmunoassay (RIA) made it possible to detect very low concentrations of CEA in blood, other body fluids, and also in normal and diseased tissues. It is excreted by certain embryonic and adult tissues in addition to adenocarcinoma of the digestive organs. Extensive studies of patients bearing primary and metastatic colorectal neoplasms have determined that its primary use is in the detection of local and metastatic cancer recurrence after initial resection of the primary tumor, through periodic postoperative analysis of CEA in serum or plasma. The notion that fluids bathing tumors in metastatic sites might contain higher levels of CEA than those found in the blood led to analysis of CEA levels in gallbladder bile from patients bearing colorectal liver metastases. It was observed that CEA levels in gallbladder bile were strikingly higher than those in serum. Furthermore , linear regression analysis of tumor volume versus gallbladder bile CEA levels in patient with liver metastases predicted that tumors as small as 1 cm would produce easily measurable gallbladder bile CEA levels as high as 41ng/ml. This data suggested that measuring biliary CEA levels in patients with primary colorectal lesions might permit detection of small, occult colorectal liver metastasis earlier than now is possible through conventional methods (computed tomography liver scanning, ultrasound, and intraoperative exploration). The results of clinical studies that CEA, although originally thought to be specific for digestive tract cancers, may be elevated in other malignancies and in some nonmalignant disorders. CEA testing is of significant value in the monitoring of patients with diagnosed malignancies in whom changing concentrations of CEA are observed. A persistent elevation in circulating CEA following treatment is strongly indicative of occult metastatic and / or residual disease. A persistently rising CEA value may be associated with progressive malignant disease and a poor therapeutic response. A declining CEA value is generally indicative of a favorable prognosis and a good response to treatment. Clinical relevance of the CEA assay has been shown in the follow-up management of patients with colorectal, breast, lung, prostatic, pancreatic and ovarian carcinoma. CEA testing recommended as a screening procedure to detect cancer in the general population; however, use of the CEA test as an adjunctive test in predicting prognosis and as an aid in the management of cancer patients has been widely accepted.

7.Cancer antigen 125(CA 125):- It is a glycoprotein of more than 200 KD, detected by monoclonal antibody. Healthy women has < 35 U/ml in their serum. It is a first marker of choice in epithelial ovarian carcinoma specially adenocarcinoma (high sensitivity 80% specificity 96%). It is useful for staging, prognosis& recurrence. It may be raised in malignancies of breast, colorectal, gastric, esophagus, liver, billiary tract, pancreas, lungs, and endometrium. After removal of ovarian tumor there is rapid decline within a week and normalize within 3-4 weeks. CA-125 value indicates prognosis, remission or relapse. Nonspecific mild rise may be seen in begin ovarian cyst.(follicular cyst), endometriosis, coelomic epithelium pathologies, cirrhosis, pleural effusion, ascites, peritonitis, pericarditis, during menstruation and last trimester of pregnancy.

8. Cancer Antigen 19-9:- It is a marker of first choice in cancer of pancreas and gall bladder. It is 210 KD glycoprotein antigen having carbohydrate on glycolipid and glycoprotein, detected by monoclonal antibody assay. The antigen is located immunologically in fetal epithelium of colon, small intestine, stomach, pancreas, liver, adult GIT and lung. Appreciable level is seen in mucin rich saliva, seminal fluid, gastric juice, amniotic fluid, urine, ovarian cyst fluid, pancreatic, gallbladder and duodenal secretion. Normal value is < 37U/ml and < 100U/ml is considered as grey zone where malignant and benign disease may overlap. In malignancy value may be > 100,000 U/L. In pancreatic tumor (sensitivity -85%, specificity -95%), cholangiocarcinoma and gall bladder carcinoma ( sensitivity 70%) it is helpful. It may have low sensitivity in colorectal, stomach, primary liver, bronchial, mucinous ovarian, uterus and mammary carcinoma. Besides diagnosis its value predicts recurrence after pancreatectomy. Nonspecific rise may occur after acute or chronic pancreatitis. (8%).

9.CA15-3:- Ca 15-3 is heterogeneous 300 KD glycoprotein antigen. The diagnostic sensitivity of the CA 15-3 for breast carcinoma is low as its elevated level is also observed in benign breast diseases and cirrhosis, acute and chronic hepatitis and in metastatic cancers of pancreas, ovary, colorectal, lung, stomach, uterus.

10.CA72-4:- Its molecular weight is more than 106 KD. This antigen was detected in fetal epithelium and also in serum of patients of various adenocarcinoas. CA 72-4 once emerged as the marker of first choice for gastric carcinoma and is thereby superior to CA19-9 and CEA. The sensitivity of CA 72-4 was found to be 38%. CA 72-4 is considered to be the multiple marker for epithelial cell derived tumors.

11.CA 19-5 & CA-50:- CA 19-5 was found to be associated with colon, pancreatic and hepatocellular carcinoma. Individually both antigens have low sensitivity. However use of both together improves sensitivity in detecting pancreatic and other carcinomas.

12.CA 549:- CA 549 is a high molecular weight circulating glycoprotein antigen associated with breast cancer. Elevated level of CA 549 is observed in serum of advanced breast cancer by using sensitive immunoassay. However, it has very low sensitivity; very low negative predictive value and high positive predict value for early breast cancer.

13.Cytokeratins/Keratins:- Keratins are remarkably diverse, highly resistant and the most conserved cytoskeletal proteins are present in all types of epithelial cells. The composition of keratin filaments ranges from a few polypeptides to 19 different polypeptides ranging from 40 to 68 KD. Keratins have gained importance as marker protein in diagnosis of tumor of epithelial origin. There may be variation in keratin expression compared to normal tissue, depending on degree of differentiation of epithelial tumors. This property of keratin allows their use in combination with other changes as markers for malignant transformation in epithelioid tumors. Keratins has 2 main applications(i)distinguish epithelial from non epithelial tumors and(ii)distinguish type of epithelial tumor. Keratin is reliable marker of (i)undifferentiated and anaplastic carcinoma(ii)infiltrating carcinoma(iii)metastasizing single carcinoma cell in suspension. It may be used for epithelial carcinomas, especially those of stratified and sqamous cell origin e.g. lung , breast, urinary bladder, thymomas and cervical carcinoma. As GItract lining from buccal mucosa to rectum including pancreas and gall bladder is of epithelial origin keratin may serve as an useful marker. Keratin has been used as a differential marker in thyroid, GItract, prostate, lung and breast.

14.Cyfra 21-1:- It is used as a marker for non small cell lung cancer (NSCLC),squamous cell carcinoma(SCC), adenocarcinoma and large cell carcinoma. This marker has highest sensitivity for SCC in lung. Both Cyfra 21-1 and CA19-9 have improved detection of adenocarcinoma of lung.
15.Calcitonin:- Calcitonin a low molecular weight peptide hormone secreted from C cells of thyroid is used as a marker, as increased level is seen in malignancies with skeletal metastasis. It is increased in medullary carcinoma of thyroid, bronchogenic carcinoma, small cell cancer of lung, breast, liver, lung, renal and carcinoid tumors.

16.Catecholamines:- Plasma and urinary epinephrine and norepinephrine are raised in Pheochromocytoma.

17.CathepsinD:- Lysosomal aspartyl protease of lysosomes is considered a potential marker for breast cancer metastasis. Cathepsin D predicts early recurrence. It has high prognostic value in node-ve breast cancer than node+ve breast cancer. Patients with low Cathepsin D value have better survival. High level of Cathepsin D enhances metastasis in breast cancer.

18.Chromogranin A:- Chromogranin A(secretogranin 1) belongs to group of closely related secretary acid protein is used as a marker to asses exocytotic sympathoadrenal activity in Pheochromocytoma. In peptide producing tumors it is raised.

19. CA27.29&CA 15-3:- Usually seen in breast cancers. May be +ve in colonic, gastric, hepatic, lung, ovarian, prostatic cancers and breast, liver, kidney diseases and ovarian cyst.

20. Circulating methylated DNA:- Circulating nucleic acids may be used as marker in early detection, follow progression. DNA is a stable molecule and detected by PCR.

21.Epidermal growth factor receptor(EGFR): -EGFR a 170 KD glycoprotein binds to epidermal growth factor(EGF). It is raised in breast cancer, gliomas, lung cancer, SCC and tumors of female genital tract. Absence of EGFR indicates a good response to Tamoxifan therapy.

22.Estrogen receptor(ER),Progesterone receptor(PR):- ER a 70 KD protein is present in mammary and uterine tissues. ER &PR belongs to receptor super gene family including receptors for thyroid hormone, vitamin D3 and retinoic acid. In breast tumor their level indicate benefit of hormone therapy. 55% to60% ER positive primary breast cancer show good hormone response. Following mastectomy high PR&ER positive tumors have longer survival. PR is more sensitive than ER.

23.Ferritin:- Serum ferritin an acute phase reactant is an intracellular protein playing a role in sequestration and storage of iron. Increased ferritin level is seen in cancers in absence of iron overload. It is increased in advanced breast, ovary, lung, colon, esophagus cancer, acute myelocytic leukemia, teratoblastoma and SCC of head and neck.

24.Homovanillic acid(HVA) & Vanillymandelic acid(VMA): -HVA &VMA are acid metabolites of catecholamines. Their increased excretion is observed in neural crest tumors. They also help in detecting and monitoring therapy in Pheochromocytoma & Neuroblastoma.

25.Hydroxy indole acetic acid (5-HIAA):- Urinary measurement helps in indole secreting tumors. Helps in diagnosis and therapy monitoring in Carcinoid tumors.

26.Her-2/neu(also known as HER,erbB-2,EGFR-2):- Seen in 20-30% of advanced breast cancers. It determine prognosis and guide treatment.
27. Human telomerase reverse transcriptase (hTERT):- It is a novel and newly available biomarker for patients with ovarian and uterine cancers. The hTERT mRNA level has a significant correlation with CA-125 and with histological finding in ovarian cancer. Serum hTERT mRNA is useful for diagnosing gynecological cancer and is superior to conventional tumor markers. Up regulation of hTERT may play an important role in the development of cervical intraepithelial neoplasia (CIN) and cervical cancer. So hTERT could be used as an early diagnostic biomarker for cervical cancer in future.

28.Interleukin-2 receptor/Tac antigen(IL-2R):- IL-2 α a 55KD glycosylated protein is seen in some types of lymphoid malignancies like T-cell leukemia. It my monitor treatment.
29. Inhibin:- Inhibin is a peptide hormone normally produced by ovarian granulosa cells. It inhibits the secretion of follicle-stimulating hormone (FSH) by the anterior pituitary gland. It reaches a peak of 772 +/-38 U/L in the follicular phase of the menstrual cycle and is normally undetectable in the serum of menopausal women. Granulosa-cell tumors produce inhibin and its serum levels reflects the tumor burden. Measurement of inhibin can be used as a marker for primary as well as recurrent granulosa cell tumor.The recent availability of markers of ovarian stroma, including melan-A and inhibin- alpha, has provided a means for the positive identification of ovarian stromal tumors, which can manifest in a myriad of histological appearances.The hormonal activity of granulosa cell tumors permits the use of a variety of serum markers in the diagnostic evaluation. Clinically the most useful serum marker for granulosa cell tumors is inhibin. Inhibin exists in 2 different isoforms. Inhibin-A and Inhibin-B. Both isoforms consists of a dimmer of 2 subunits, the alpha and beta subunits. Inhibin usually becomes no detectable after menopause. However, certain ovarian tumors mostly mucinous epithelial ovarian carcinoma and granulosa cell tumors produce inhibin. An elevated level in a postmenopausal women or a premenopausal women presenting with amenorrhea and infertility is suggestive of the presence of a granulosa cell tumor, but not specific. Inhibin levels can also be used for tumor surveillance after treatment to assess for residual or recurrent disease.

30.Lipid associated sialic acid in plasma(LASA-P):- Increased level is seen in malignancies of breast, GItract, lung, leukemia, lymphoma, Hodgkin’s and melanoma(sensitivity vary -77% to97%). Slight increase is seen in many inflammatory diseases indicating poor specificity.
31. Lysophospatidic acid:- It stimulates cancer cell proliferation, intracellular calcium rise and tyrosine phosporylation. It is found in ascitic fluid of ovarian cancer.

32.L1(CAM):- It correlates with stage and grade of ovarian cancer and response to chemotherapy.

33.LDH(lactate dehydrogenase):- Though one of the first marker clinically used may be raised in many cancers. It is currently used in monitoring some leukemias and lymphomas.

34.Monoclonal immunoglobulin/Paraprotein:- Monoclonal immunoglobulin content is of value in diagnosis and monitoring management of plasma cell tumors like Multiple myeloma, Waldenstrom’s macroglobulinemia, plasma cytoma, B cell leukemias and lymphomas.

35.Mitf (Microphthalmia transcription factor):- It is important in melanocyte development and growth. It is tried in determining disease stage and survival, detect sub clinical metastasis and outcome of treatment.

36.Mullerian inhibiting substance(MIS):- MIS is produced by granulosa cells in the developing follicles. It has emerged as potential tumor marker for granulosa cell tumors. As with inhibin, MIS is typically undectable in postmenopausal women. The elevated MIS level is highly specific for ovarian granulosa cell tumors. However, this test is not commercially available for clinical use.

37.Neuron specific enolase(NSE):- NSE, the gamma subunit of enolase enzyme is present in neurons & neuroendocrine cells.NSE is raised in glucagonoma, insulinomas, carcinoid tumor, pheochromocytoma, medullar carcinoma of thyroid, oat cell carcinoma, small cell and other lung cancers. It is marker of 1st choice in SCLC.NSE monitoring is used in assessing prognosis and therapeutic response in85% of neuroblastoma and SCLC.

38.NMP-22:- Not widely used. Urine level helps in diagnosis and recurrence of bladder tumors(>10 units/ml).

39.Oncogene P21 RAS:- RAS ,one of the transformation inducing gene belonging to family of cellular oncogens(c-ras) frequently seen in human solid tumors like colorectal carcinoma, large adenomas, bladder and lung tumors.

40.Prostate specific antigen(PSA):- PSA known earlier as gammaseminoprotein is 34 KD single chain glycoprotein (93% amino acid, 7% carbohydrate) , a monomer made up of 240 amino acid residue. It is a neutral serine protease, having trypin and chymotrypsin like activities belonging to glandular kalkrein family. Synthesized from prostate epithelium. Small amount of PSA released to circulation form complexes with different protease inhibitors detected in serum and seminal fluid. PSA-ACT complex (major immunoreactive form 80-90%), PSA-AT (α-1 antitrypsin) PSA-PCI(protease C inhibitor ) and PSAα2M(α-2 macroglobulin) are different complexes. The remaining PSA are free immunoreactive form(5-15%). PSA is most useful and clinically relevant marker for prostatic cancer. It is useful for early detection, prevention and assay efficacy of treatment. PSA is synthesized in low quantity by normal prostate, mild quantity in inflamed or hypertrophied prostate, prostatic trauma, after ejaculation and in large quantity by malignant prostate. Due to overlap at times there may be difficulty to distinguish between BPH and early cancer. However combined with digital rectal examination and transrectal ultrasound PSA proves useful in adenocarcinoma besides biopsy. The value of PSA also increases with age and there is correlation between total and free PSA. Indian males have low level as compared to other countries. Though the normal cut off value is 4ng/ml it increases with age. Use of age specific reference value will improve diagnostic efficacy. Clinical analysis of molecular forms of PSA, free PSA, or free PSA/total ratio are useful to differentiate begin from malignant conditions. Other markers in prostatic cancer are PAP, Alkaline phosphates (ALP), PSMA,
Zn-alpha-2-glycoprotein, leucine amino peptidase, lactic dehydrogenase.

41.Prostate acid phospatase(PAP):- Acid phosphates activity is 200 times more abundant in prostate tissue than in any other tissue. Acid phosphatase prostatic fraction is useful only in staging apparently localized disease i.e., primary prostate cancer before definitive therapy such as radical prostatectomy. Its activity in serum can be estimated by several synthetic substrates, but now specific antibodies are available for immunoassay. The enzymatic assay appears superior to the immunoassay in this context. Interest in acid phosphates assay in serum as a measure of prostatic cancer staging has decreased with the availability of more sensitive and specific PSA assay.

42. Parathyroid hormone related peptide(PTH-RP):- Elevated plasma level is seen in cancers having hypercalcemia. It helps to differentiate primary hyperparathyroidism, sarcoidosis, vitamin-D, squamous cell carcinoma of renal, bladder and ovarian cancers.
43.PS 2:- PS2, a low molecular weight cysteine rich protein is raised in 50% of breast tumors. Its expression indicates better prognosis than ER and PR. It is also seen in normal stomach mucosa and ulcerative disease of GItract.

44. PSMA (Prostate specific membrane antigen):- Though not used, may rise with age and serum level indicate prostate disease.

45. S-100:- Though not widely used, may help in diagnosis of metastatic melanomas.

46.Tissue polypeptide antigen(TPA):- TPA regarded as a marker of cell proliferation, is a mixture of proteolytic fragments cytokeratins 8,18,and19. These fragments are released during necrosis and lysis of cancer cells. TPA is regarded as a broad spectrum epithelial marker. Moderate elevation occurs in many diseases and pregnancy. Marked elevation is reported in cancers of breast, lung, gastrointestinal, urological and gynecological conditions.TPA though sensitive but not specific. TPA with CEA help in monitoring lung, breast, bladder, colorectal and ovarian carcinomas.

47. Tumor suppressor gene P53:- P53, a 53 KD nuclear phospoprotein acts as tumor suppressor by inhibiting cell proliferation and plays a role in cellular apoptosis.P 53 gene mutation seen in 50% of all cancers like breast, colon, ovary, lung and esophagus.

48.Squamous cell carcinoma(SCC) antigen:- SCC antigen, a 48KD protein is purified from uterine cervix. It is raised in squamous cell cancer of head & neck, lung, esophagus and anal canal. Highest level is found in metastasis. It is elevated in advanced cervical cancer, determine progression or regression following chemotherapy. Combined use of CEA, NSE, SCC antigen increase sensitivity in detection and monitoring lung cancers.

49. Thyroglobulin:- Used after removal of thyroid to find recurrence. It is elevated in many thyroid diseases. In some antibody is formed against thyroglobulin. So level of antithyroglobulin antibody is measured at the same time.

50. Topoisomerase II:- Topoisomerase II expression is detected in tumor samples by immunohistochemistry and has emerged as a promising, clinically relevant biomarker for survival in patients with advanced epithelial ovarian cancer.

51. TA-90:- Recently on trial to diagnose metastatic melanomas. This protein is found on outer surface of melanoma cells. Its use is studied in colon and breast cancer.

52. Other Gynecological markers:- Other markers in many gynecological conditions are-
Urinary gonadotrophin fragment, Tumor associated trypsin inhibitor, Cyclin E, Mesothelin, HE4, Osteopontin, Ineterleukin 8, Vascular endothelial growth factor(VEGF), Macrophage colony stimulating factor, Insulin like growth factor-binding protein-3, OVX, NB70/K, HMFGR (human milk fat globule)

METHODS:- Common methods used to identify tumor proteins are-
1. Immunohistochemistry- Traditionally most methods have used monoclonal antibodies and immunohistochemistry. They can be used directly in tumors or serum, bonemarrow, lymphnodes.
2. Reversed transcriptase and polymerase chain reaction(RT-PCR)


USEFULNESS:- Tumor markers are usually used for--
1. Detection-Screening in asymptomatic cases for early diagnosis.
2. Diagnosis-Differentiating malignant from benign condition.
3. Monitor-Predict effect of therapy and detect recurrence.
4. Prognosis-Choosing therapy and predict tumor behavior.
5. Therapy-Directing cytotoxic agents to marker containing cells.

SUMMARY:-
Tumor markers are biomolecules released or formed during neoplastic process. Though an ideal marker is yet to be identified they aid in detection, diagnosis, monitor response and recurrence. They may be raised in some nonmalignant conditions.
In urinary bladder tumor BTA and NMP-22 are used along with urine cytology and cystoscopy. In advanced cancers CEA, CA-125,CA 19-9 & TPA are raised.
In breast cancers ER,PR and HER/neu are used for diagnosis. In advanced cases follow-up and recurrence are detected by CA15-3, CA 27-29 & CEA.
In colorectal advanced cancers CEA & ca19-9 are elevated, but neither is helpful for screening test. They are used for follow-up and recurrence.
Gestational trophoblastic diseases show elevated βHCG.
In liver cancers AFP is used for screening, diagnosis and follow-up.
In lung cancers no marker is useful for screening. CEA is raised in non small cell cancer and NSE in small cell cancers and used for evaluation of treatment.
Though no marker is useful for screening TA-90, S-100 and other markers help to find metastasis, follow-up and prognosis.
In multiple myeloma immunoglobulins,β2M are helpful.
In ovarian epithelial cancer CA-125 is usually elevated. Others like CA72-4 & LASA-P are raised. In ovarian germ cell tumor βHCG and AFP are raised.
In pancreatic cancer though no marker is helpful for screening CA 19-9 & CEA are used.
For prostatic malignancy PSA is commonly used. Markers like PSMA, chromogranin-A and PAP are also useful.
Though no marker has developed for stomach cancer CEA,CA 72-4 & 19-9 are raised at times.
For testicular tumor βHCG is elevated in seminomas where as AFP or βHCG or both are raised in nonseminomas.

CONCLUSION:-
Though all tumor marker are not ideal biomarkers their judicious use following evidence based medicine are clinically helpful. Inspite of nonspecificity of wide spectrum of available markers, their potential role in monitoring entire cancer therapeutic course is clinically relevant.

CLINICAL FOCUS:-
 Tumor markers are substances which indicate probable presence of malignancies.
 Few are specific, most of them are nonspecific. Many are seen in nonmalignant conditions.
 All of them are classified into various biochemical groups.
 Though tried since long not a single one fulfill the criteria of ideal marker.
 AFP is specific for liver cancers.
 BTA,NMP-22,CEA,CA125,CA19-9, TPA indicate bladder cancer.
 TA-90,S-100 indicate melanoma.
 ER,PR,HER/neu,CA15-3,CA27-29, CEA are indicative of breast cancers.
 PSA,PSMA,PAP are raised in prostatic conditions.
 CEA,CA72-4,CA19-9 are raised in gastric malignancies.
 CEA,CA 19-9 are increased in pancreatic and colorectal cancers.
 CEA,NSE are raised in lung cancers.
 CA-125,βHCG and AFP are raised in ovarian conditions.
 In testicular tumors βHCG &AFP are raised.
 They are detected by immune assay or RT-PCR.
 Few are used for screening asymptomatic cases while others are helpful for diagnosis, staging, prognosis, response to resection or chemotherapy and recurrence.


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Jul22
ANALYSIS OF SERUM LIPID CHANGES IN PLASMODIUM FALCIPARUM MALARIA
Malaria is the most important of the parasitic diseases of humans with transmission in more than 100 countries, affecting more than 1 billion people and causing 1- 3 million deaths each year. It is a major cause of morbidity and mortality in tropical regions. Plasmodiurn falciparum infection is a prime cause of concern in India where a resurgence of infection is being witnessed in the present decade. The state for Orissa with a population of 4% that of India, accounts for 25% of all cases of malaria .Orissa also bears the highest mortality rate of 35% of total malaria deaths in the country. Cerebral malaria is the most dreaded form of malaria, carrying a mortality rate of 50% even in treated patients. The SPR (Slide positivity rate) in Orissa is 11.89% of which 84% are pl. falciparum and death rate is 35% of the total mortality in the country. WHO has fixed a goal to reduce malarial mortality by 50% by 2010.
Fever is a common presentation of patients in developing countries like India and most of which are of infectious etiology. Thus malaria is one of the leading causes. The clinical profile of falciparum malaria involves hepatic, renal, circulatory, respiratory and cerebral features . There are several clinical and biochemical parameters, which have been claimed to predict outcome with reasonable degree of accuracy. Among them TNF- α in falciparum malaria mediate different biochemical changes.
In the past, changes in lipid profile have been observed in malaria (Vernes et al, 1980, Nissen - Ehle et al, 1990, Parola P et al 2004). Most of the time it is not possible to ascertain the etiologic agent in a case of pyrexia, as malaria parasites are difficult to be found out in blood . Hence the above mentioned acute phase reactants mediated changes in lipid profile may be considered as an indirect evidence of infection by different etiologic agents. As it is difficult and costlier affair to measure TNF - α and other acute phase reactants and lipid profile measurement is a cheap and widely available alternative, its estimation may be useful in diagnosing, differentiating or predicting outcomes in malaria.


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