POLY ARTICULAR GOUT-A CASE REPORT
Posted by on Sunday, 12th February 2012
Unusual case of poly articular gout-a case report.
Abstract-
Gout is a common inflammatory arthritis caused by deposition of monosodium urate crystals in the joints. It classically affects the first metatarsophalangeal joint and less commonly other joints, such as wrists, elbows, knees and ankles.
We report the case of a 65-year-old man with tophaceous polyarticular gout, soft-tissue involvement of elbow joint with secondary infection leading to septicemia.
Key words
Gout, monosodium urate crystals, tophi, arthropathy,Febuxostat,Colchicine
Introduction-
Gout is a common disorder of uric acid metabolism, characterized by recurrent episodes of inflammatory arthritis, tophaceous soft tissue deposits of monosodium urate crystals, uric acid renal calculi and chronic nephropathy. We report the case of a 65-year-old man suffering from tophaceous polyarticular gout and soft-tissue involvement, presenting with ulcerated tophi overlying the left elbow. We also emphasize the disabling effects of the untreated hyperuremic arthropathy.
Case presentation
A 65-year old man with a long-standing history of tophaceous gout and several recurrent episodes of arthritis during the past five years presented with a large, painful, ulcerated tophus located on the left elbow joint to the emergency department. He tried a course of non-steroidal anti-inflammatory drugs (NSAIDs) without improvement.
On physical examination he had a mild fever of 37.8°C. A grayish, voluminous and ulcerated nodule containing chalky material was located on the left elbow. Further examination revealed multiple other tophi overlying the 4th and 5th PIP joints (proximal interphalangeal joint) of his right hand and the first interphalangeal joints of his left hand(Figure 1). Other joints involved were wrists, elbows, ankles, interphalangeal and metatarsophalangeal joints of the feet and heels. Many joints were also deformed. The first metatarsophalangeal joint of his left foot was totally nonfunctional.
Laboratory workup revealed leukocytosis (11.000/mm3), elevated C-reactive protein (60.21 mg/dl) and elevated serum uric acid (11 mg/dl) and normal serum creatinine (0.9mg/dl). Radiographs of the hands showed showing soft tissue swelling and destruction of both wrist, left IP thumb, right 4th and 5th PIP joints, calcified tophi seen in right 2nd MCP joint(meta carpo phalangeal joint)(Figure 2). A culture from the ulcerated tophus was positive for staphylococcus aureus (Methicillin sensitive). Two days after admission, the tophus burst releasing a viscous, chalk-like material. Polarized microscopy confirmed presence of needle shaped monosodium urate crystals (Figure 3).
Antibiotic treatment with IV Ciprofloxacin (1000 mg/day) and intravenous administration of NSAIDs (Diclofenac 100 mg/day) was initiated.
A surgical debridement with lavage of the joint was performed. Debridement was also performed on the minor ulcers. Five days after admission treatment with Febuxostat (80 mg/day) along with Colchicine 0.5mg twice daily was initiated. The patient improved clinically and was discharged two days later. Six months after treatment, he remains symptom free.
Discussion:
Gout is the most common inflammatory arthropathy, reported to affect 2.13% of the population of the United States of America in 2009 [1]. Older age, male sex, postmenopausal state and black race are related to a higher risk for development of the disease [2]. Elevation of uric acid levels above the saturation point for urate crystal formation (6.8 mg/dl) usually results from an impaired renal uric acid excretion and although necessary, it is not sufficient to cause gout. Hyperuricemia and gout can be attributed to uric acid elevating drugs, genetic polymorphisms in genes controlling renal urate transport and predisposing dietary factors, such as consumption of red meat, seafood, alcohol and fructose containing soft beverages [3]. Other conditions associated with the disease include insulin resistance, obesity, hypertension, renal insufficiency, congestive heart failure, and organ transplantation [2].
Over time, poorly controlled gout may progress to a chronic phase, characterized by polyarticular attacks, painful symptoms between acute flares and monosodium urate crystal deposition (tophi) in soft tissues or joints [2]. Tophi are typically found on the helix of the ears, on fingers, toes, wrists and knees, on the olecranon bursae, on the Achilles tendons and also rarely on the sclerae, subconjuctivally, [4] and on the cardiac valves [5]. They can cause pain and dysfunction and are rarely associated with ulcerations [6], bone fractures [7], tendon and ligament rupture [8], carpal tunnel [9] and other nerve compression syndromes [10]. Differential diagnosis for subcutaneous or articular nodules includes septic arthritis, synovial cysts, nodal osteoarthritis, rheumatoid arthritis, sarcoidosis, lymphoma or neoplasms [11]. Synovial fluid or tophus aspiration permits diagnosis through demonstration of negatively birefringent monosodium urate crystals [2].
Treatment options for acute gouty attacks include dietary and lifestyle modifications, NSAIDs, colchicine, oral or topical steroids and corticotropin (ACTH). Interleukin-1 (IL-1) antagonists, such as anakinra, a human recombinant IL-1 receptor antagonist and canakinumab, a monoclonal antibody against IL-1β, have also shown promising results in the treatment of refractory cases or cases intolerant to classical therapy [2]. Even without treatment acute attacks usually resolve spontaneously within seven to 10 days. Normalizing hyperuricemia is of cardinal significance for the control of recurrent attacks and for the regression of tophi. This is achieved with drugs, which either favor uric acid excretion (probenecid), convert uric acid into soluble allantoin (pegloticase), or inhibit uric acid production (allopurinol, febuxostat) [2].
Surgical treatment is seldom required for gout and is usually reserved for cases of recurrent attacks with deformities, severe pain and joint destruction [11]. The main indication for surgery in patients with tophaceous gout is sepsis or infection of ulcerated tophi, followed by mechanical problems, confirmation of diagnosis and pain control [12]. Removal of tophaceous deposits from the hands can be achieved through tenosynovectomy for heavily infiltrated tendons, through a soft-tissue shaving technique for heavy skin infiltration with ulceration and draining fissures [13], or through more complex surgical approaches involving large skin incisions and excision of the tophi [14]. A hydrosurgery system applying a highly pressurized saline stream has also been used with good results for the debridement of tophi [15]. In the early stages, surgical arthroplasty can be carried out, but simple enucleation of the tophi may lead to complications such as skin necrosis, tendon and joint exposures [11]. Amputation is always a valid option for untreatable and infected ulcerations [16].
Conclusion
Secondary infection of tophaceous gout are not uncommon can lead to septicemia. Surgical treatment is required for such cases along with medical therapy.
References:
1.Brook RA, Forsythe A, Smeeding JE, Lawrence Edwards N. Chronic gout: epidemiology, disease progression, treatment and disease burden. Curr Med Res Opin. 2010;26:28132821. 2.Neogi T. Clinical practice. Gout. N Engl J Med. 2011;364:443452.
3.Lee SJ, Terkeltaub RA, Kavanaugh A. Recent developments in diet and gout. Curr Opin Rheumatol. 2006;18:193198.
4.Sarma P, Das D, Deka P, Deka AC. Subconjunctival urate crystals: a case report. Cornea.2010;29:830832
5.Iacobellis G. A rare and asymptomatic case of mitral valve tophus associated with severe gouty tophaceous arthritis. J Endocrinol Invest. 2004;27:965966.
6. Patel GK, Davies WL, Price PP, Harding KG. Ulcerated tophaceous gout. International Wound Journal. 2010;7:423427.
7.Nguyen C, Ea HK, Palazzo E, Liote F. Tophaceous gout: an unusual cause of multiple fractures. Scand J Rheumatol. 2010;39:9396.
8.Iwamoto T, Toki H, Ikari K, Yamanaka H, Momohara S. Multiple extensor tendon ruptures caused by tophaceous gout. Mod Rheumatol. 2010;20:210212.
9.Ali T, Hofford R, Mohammed F, Maharaj D, Sookhoo S, van Velzen D. Tophaceous gout: a case of bilateral carpal tunnel syndrome. West Indian Med J. 1999;48:160162.
10.Tran A, Prentice D, Chan M. Tophaceous gout of the odontoid process causing glossopharyngeal, vagus, and hypoglossal nerve palsies. Int J Rheum Dis. 2011;14:105108. 11.Khandpur S, Minz AK, Sharma VK. Chronic tophaceous gout with severe deforming arthritis.Indian J Dermatol Venereol Leprol. 2010;76:6971.
12.Kumar S, Gow P. A survey of indications, results and complications of surgery for tophaceous gout. N Z Med J. 2002;115:U109.
13. Lee SS, Sun IF, Lu YM, Chang KP, Lai CS, Lin SD. Surgical treatment of the chronic tophaceous deformity in upper extremities - the shaving technique. J Plast Reconstr Aesthet Surg. 2009;62:669674.
14.Tripoli M, Falcone AR, Mossuto C, Moschella F. Different surgical approaches to treat chronic tophaceous gout in the hand: our experience. Tech Hand Up Extrem Surg. 2010;14:187190.
15.Lee JH, Park JY, Seo JW, Oh DY, Ahn ST, Rhie JW. Surgical treatment of subcutaneous tophaceous gout. J Plast Reconstr Aesthet Surg. 2010;63:19331935.
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16.Ertugrul Sener E, Guzel VB, Takka S. Surgical management of tophaceous gout in the hand.Arch Orthop Trauma Surg. 2000;120:482483.
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LIPID PROFILE IN FALCIPARUM MALARIA
Posted by on Sunday, 12th February 2012
TITLE-SERUM LIPID PROFILE IN FALCIPARUM MALARIA & ITS PROGNOSTIC SIGNIFICANCE
AUTHORSB.K.BARIK, S.GURU, B.N.PATNAIK,P.DAS
INSTITUTEI M S & SUM HOSPITAL, BHUBANESWAR
MATERIALS & METHODS---
The present study was conducted among 30 cases of complicated & 30 case of uncomplicated malaria admitted to this Hospital during the period from January 2009 to December 2010.
AIM & OBJECTIVE
To find out changes in Serum lipid profile in Falciparum Malaria & correlate it with prognostic significance
A control group of 45 cases were taken matching the criterias as far as possible from healthy volunteers.
Cases of DM, CKD &Hypertension were excluded from the study.
Contd
.
Serum lipid profile(Total cholesterol, Triglyceride, HDL, LDL, VLDL) were estimated on admission, after diagnosis after 8 hours over night fast.
The method used was Dual Precipitation Method.
All lipid parameters ere repeated after 7 days of treatment of all cases.
Besides all clinical examination & other routine laboratory investigations were done.
OBSERVATION
Age & Sex distribution in Cases and Control
DISCUSSION-
In our study cases belonged to younger group with male predominance.
In complicated cases Renal, Hepatic & CNS involvement was predominant.
In complicated cases TG& VLDL was high that decreased after 7 days of treatment comparing uncomplicated cases.
High TG & VLDL was associated with hepatic & renal dysfunction.
CONCLUSION-
Serum TG can be considered most important prognostic indicator with many variations in lipid fractions.
Serum HDL is also good indicator with low sensitivity but high specificity.
Serum TG level returns to baseline after 7 days indicating response assesment
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HAV & OTHER VIRAL INFECTIONS OF LIVER
Posted by on Thursday, 22nd July 2010
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(2΅w/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 210 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 immunoglobulins (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 dont 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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OPPORTUNISTIC INFECTION IN HIV/AIDS
Posted by on Thursday, 22nd July 2010
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 Burgers 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 Johnsons 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 < 300L 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. Chagas 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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TUBERCULOUS MENINGITIS
Posted by on Thursday, 22nd July 2010
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 physicians 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 criterias. 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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