A case of PUO

ByProf.S.Tito’s Unit

• Jayaarthi 26 yr female, married,admitted with c/o fever – 5months,intermittent,low grade with chills and rigorsH/o loss of wt& appettite H/o Cough with expectoration – 3months,mucoid,non foul smelling, mild to moderate amount not ass with haemoptysis H/o Breathlessness ,grade-2,no diurnal variation H/o leucorrhea on and off NoH/o headache,vomiting,abdominal pain ,loose stools, burning micturition ,jaundiceNoH/o any bleeding tendencies, rec throat infections, NoH/o jt pain, rec oral ulcers, skin rashes, loss of hair

Past History:No H/o DM,HT,cardiac illness,H/o Pul TB diagnosed and treated with ATT –Cat-I, and declared cured

Obstetric History:No H/o recurrent abortionH/o full-term normal delivery 6 months before

Family History:No H/o DM, HT, TB, Connective tissue disorder & malignancy

Menstrual History:Scanty ,irregular

On examination : pt consc,oriented,febrile,pallor,emaciated No cyanosis ,no clubbing, no

lymphadenopathy,not icteric no oral ulcers,no pedal edema, no skin rashes, no

external markers of TB

Respiratory examination:Trachea shifted to rt side,apical impulse normal in

position ,movements of chest wall diminished more in the rt side. B/l coarse crepts

CVS:S1S2 normaly heard ,No murmur

Abdomen:soft, No organomegaly

CNS:No neurological deficit, no meningeal signs

Investigations21/9/08 30/9/08

Hb 7 9.4

Tc 7800 8,600

DC 75/25 60/36/4

ESR 10/22 20/42

Platelets 3.5lakh 1.2lakhs

MCV 88.2 97.2

MCH 25.1 27.2

MCHC 32 29.4

RBS 60 69

UREA 22 13

Creati 0.9 0.8

Na/K 135/3.7 141/3.5

Urine –alb Nil Nil

U-sug Nil Nil

U-deposit 1-2pus cells 3-4puscells

PS and QBC for MP Neg Neg

MSAT Neg Neg

Widal NEg Neg

Sputum for AFB Neg Neg

Sputum C/S Pseudomonas S to GM and cipro

KlebsiellaS to Amika and cipro

USG ABD & Pelvis Normal study Rt renal calculi(4mm)

ANA ,ASO,RF Neg Neg

CRP 96 92

Sr Bil 0.8 0.9

T.pro 7 6.4

alb 3.8 3.6

Sr.calcium 9

Sr.ADA 24.3(negative)

HIV Neg Neg

VDRL Neg Neg

Peripheral smear study Normocytic hypochochromic anemiaNo immature cells

CT Chest: Rt Upper lobe bullous lesion ,Rt middle and lower lobe consolidation with ectatic changes lt upper lobe and lower lobe

ECHO: Normal study ,No vegetations

Blood Culture(thrice): Negative for organisms

IgM for brucellosis: Negative

Treatment Given: Inj.Cefotaxime,chloroquine,Doxy,Metranidazole,Nebulization, cat-II ATT started

cxr

TRC Opinion(30/9/08): Sputum AFB repeat neg; Sputum C/s for TB taken. Even

though pt is sputum AFB negative with symptoms of TB with increasing infiltrates in CXR advice to con ATT-CatII Even after all these treatment measures pt continued with fever but breathlessness,Cough and expectoration subsided.pt advised to continue cat-II ATT until c&s report arrives.

DIAGNOSIS

• INH – resistant pulmonary tuberculosis • Pt referred to Tambaram Sanatorium for

further management

On further follow-up

• Treatment giveninj.SM 0.75g 3/wkCap.Rifampicin 450mg OD dailyT.Ethambutol 800mgOD dailyT.Ciprofloxacin 500mg BD daily PAS 10g OD daily

Fever subsided, anorexia improved, wt gained

• Sputum smear done at the end of 3 and 4th month turned out be POSITIVE

• Sputum c&s for ATT at the end of 3rd report awaited.

FINAL DIAGNOSIS

• SUSPECTED MDR-TB

T

NTF Presentations for RNTCP Sensitization First edition 10th Nov 06

Problem of TB in India• Estimated incidence

-75 new smear positive PTB cases/1lakh population per year • Estimated prevalence of TB dise– 1.7 million new smear positive cases in 2000

• Estimated mortality– Over 1000 deaths a day– 2 deaths every 3 minutes

Gopi P et al (TRC), IJMR, Sep 2005

• Prevalence of TB infection – 40% (~400m) infected with M. tuberculosis (with a 10% lifetime risk

of TB disease in the absence of HIV)

• Estimated Multi-drug resistant TB– < 3.4% in new cases– 12% in re-treatment cases

• TB-HIV– 10-15% annual risk (60% lifetime risk) of developing active

TB disease in PLWHA– Estimated 5% of TB patients are HIV infected

DEFINITIONS OF DRUG RESISTANCE

DR-TB is confirmed through laboratory tests that show that the infecting isolates of Mycobacterium tuberculosis grow in vitro in the presence of one or more antituberculosis drugs. Four different categories of drug resistance have been established:

• Mono-resistance: resistance to one antituberculosis drug.

• Poly-resistance: resistance to more than one antituberculosis drug, other than both isoniazid and rifampicin.

• Multidrug-resistance: resistance to at least isoniazid and rifampicin.

• Extensive drug-resistance: resistance to any fluoroquinolone, and at least one of three injectable second-line drugs (capreomycin, kanamycin and amikacin), in addition to multidrug-resistance.

Resistance incidence

• INH resistance 18%• RIFAMPICIN resistance 2%• Failure rate even after complete trt under cat1

&cat2 tretment are 2% and 6% respectively.• New cases 1-3%• Previously treated cases 12-17%

WHEN TO SUSPECT MDR-TB

1.cat1/cat3 treatment failure

2.Even after 4 months of cat2 treatment sputum smear is positive

Exclusion: 1.<15 years of age

2.Having had >1month treatment with any secondline drug

3.Source of contact is MDR-TB

Common treatment strategies for DR-TB

Standardized treatment Representative DRS data in well-defined patient populations are used to design the regimen. All patients in a patient group or category receive the same regimen.

Standardized treatment followed by individualized treatment

Initially, all patients in a certain group receive the same regimen based on DST survey data from representative populations. The regimen is adjusted when DST results become available (often DST is only done to a limited number of drugs).

Empirical treatment followed by individualized treatment

Each regimen is individually designed on the basis of patient history and then adjusted when DST results become available (often the DST is done of both first- and second-line drugs)

HOW TO BUILD A TREATMENT REGIMEN FOR MDR-TB

Guidelines for the programmatic management of drug-resistant tuberculosisEmergency update 2008 WHO– page60

• Confirmed MDR-TB.

• Suspected MDR-TB –pt may be started on Category IV treatment before MDR-TB is confirmed only if representative DST surveys or other epidemiologic data indicate a very high probability of MDR-TB

• Poly-resistant TB. Some cases of poly-resistant TB will require Category IV treatments. These patients require prolonged treatment (18 months or more) with first-line drugs combined with two or more second-line drugs .

• Category –II Failure Cases

CATEGORY IV Regimen

Culture and DST results and further action

RNTCP Grouping Drugs

Group 1: First-line oral anti-TB agents Isoniazid (H); Rifampicin (R); Ethambutol (E); Pyrazinamide (Z) Group 2: Injectable anti-TB agents Streptomycin (S); Kanamycin (Km); Amikacin (Am); Capreomycin (Cm); Viomycin (Vm).

Group 3: Fluoroquinolones Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin (Lvx); Moxifloxacin (Mfx); Gatifloxacin (Gfx)

Group 4: Oral second-line anti-TB agents Ethionamide (Eto); Prothionamide (Pto); Cycloserine (Cs); Terizadone (Trd); paraaminosalycilic acid (PAS); Thiacetazone (T)

RNTCP CATEGORY IV REGIMEN(DOTS+ strategy)

6 (9) Km Ofx Eto Cs Z E / 18 Ofx Eto Cs E

Follow up

• Sputum smear to be done monthly during IP and every three months during CP

• Sputum culture to be done at the end of the months 3, 6,12, 18 and 24. If any of the cultures in the last three quarters becomes positive monthly culture to be done.

conversion

• Patients will be considered culture converted after having two consecutive negative cultures taken at least one month apart.

• Similarly patients will be considered smear converted after having two consecutive negative smears taken at least one month apart.

MDR-TB requiring surgery

• Absence of clinical or bacteriological response to chemotherapy despite six to nine months of treatment with effective antituberculosis drugs;

• High risk of failure or relapse due to high degree of resistance or extensive parenchymal involvement;

• Morbid complications of parenchymal disease e.g. haemoptysis, bronchiectasis, bronchopleural fistula, or empyema;

• Recurrence of positive culture status during course of treatment;

• Relapse after completion of anti-tuberculosis treatment. • If surgical option is under consideration at least six to nine

months of chemotherapy is recommended prior to surgery

X-DR TB

• Extensive drug-resistance: resistance to any fluoroquinolone, and at least one of three injectable second-line drugs (capreomycin, kanamycin and amikacin), in addition to multidrug-resistance.

XDR-TB IN INDIA

• Extreme drug-resistant TB (XDR-TB) It is known as the worlds most untreatable form of tuberculosis

• Study at Hinduja hospital Mumbai showed 32% suffered from multiple drug resistance (MDR-TB), and 8% of them were XDR-TB cases.

• Mortality rate of XDR-TB patients in the study is known to be 42%. "XDR-TB is a growing problem in India affecting mostly young, working-age people .

1. Use any Group 1 agents that may be effective.2. Use an injectable agent to which the strain is susceptible and consider an extended duration of use (12 months or possibly the whole treatment). If resistant to all injectable agents, it is recommended to use one the patient has never used before.3. Use a later-generation fluoroquinolone such as moxifoxacin.4. Use all Group 4 agents that have not been used extensively in a previous regimen or any that are likely to be effective.5. Use two or more agents from Group 5.6. Consider high-dose isoniazid treatment if low-level resistance is documented.7. Consider adjuvant surgery if there is localized disease.8. Ensure strong infection control measures. 9. Treat HIV

MANAGEMENT GUIDELINES FOR PATIENTS WITH DOCUMENTED XDR-TB

Initiating ART (Anti-Retroviral Therapy) in patients with MDR- TB

CD 4 Cell count ART Recommendation Timing of ART

< 200 cells/mm3 Recommend ART At 2 weeks or as soon as thetreatment for MDR TB is tolerated

200-350 cells/mm3 Recommend ART After 8 weeks of initiation of trt

> 350 cells/mm3 Defer ART Monthly evaluate and every 3 month CD4 testing

Not available Recommend ART Between 2 to 8 weeks of starting