Tuberculosis and diabetes mellitus – what’s

next ? WS 4 Tuberculosis and other Lung Infection

Alila Htl Solo, sept 11st-12th 2019

Yani Jane Sugiri dr, SpP(K)

Department of Pulmonology and Respiratory Medicine

Saiful Anwar General Hospital

Faculty Medicine Brawijaya University

Malang, Indonesia

Outline • Introduction • Epidemiology • Characteristic of clinical symptoms Tuberculosis and Diabetes Mellitus • Immunity disorder in Diabetes Mellitus patients • Radiologic Manifestations of patients with TB and DM • Screening for Tuberculosis among patients with Diabetes Mellitus • Screening for Diabetes among patients with Tuberculosis • Diabetes and Drug Resistant TB. • Plasma Consentration of AntiTuberculosis • Monitoring and evaluation • Summary

2

Introduction The association between DM and TB was 1st

documented by Avicenna (980-1027 AD) over 1000 years ago.

The link of DM and TB is more prominent in developing countries where TB is endemic and the prevalence of DM is rising

The definite pathophysiological mechanism of the effect of DM as a predisposing risk factor for TB is unknown

3

Epidemiology

4

Epidemiologi DM

5

Characteristic of clinical symptoms Tuberculosis and Diabetes Mellitus • The symptoms of DM (polyuria, polydipsia, polyphagia, unexplained

weight loss, extreme tiredness, slow wound healing) Some of the symptoms of DM may overlap or similar with symptoms of TB

• Higher body weight

• More symptoms but did not have a more severe form of TB

• Extra-pulmonary involvement has been reported to be less common

• Higher frequency acid fast bacilli positive? Or negative sputum smears or not related ?

6

PENEMUAN KASUS TB PADA PENYANDANG DM

Penapisan TB pada penyandang DM:

1. Anamnesis gejala TB, dan

2. Foto rontgen dada

Survei Prevalensi TB Nasional, 2013

Gejala

TB

Abnormalitas pada

Rontgen dada

Dapat diperiksa

dahaknya

BTA pos BTA neg

Kultur

pos

MTB pos

Yes No 3,878 6 16 22

Yes Yes 4,524 105 110 215

No Yes 6,664 52 133 185

Yes NA 401 2 2 4

Total 15,46

7 165 261 426

Hampir 50% pasien TB dengan konfirmasi bakteriologis yang ditemukan, tidak bergejala namun foto rontgen dada menunjukkan abnormalitas

Immunity disorder in Diabetes Mellitus patients

8 Schuetz P, Castro P, Shapiro NI. Diabetes and Sepsis: Preclinical Findings and Clinical Relevance. Diabetes Care, Vol 34, March 2011

Radiologic Manifestations of patients with TB and DM

• (

9 (Ruslami R, Aarnoutse RE, Alisjahbana B, van der Ven AJAM, van Crevel. Implications of the global increase of diabetes for tuberculosis control and patient care. Tropical Medicine and International Health, 2010:15;11: 1289–1299)

(Patel AK, Rami KC, Ghanchi FD. Radiological presentation of patients of pulmonary tuberculosis with diabetes mellitus. Lung India ,2011. Vol 28: Issue 1:70)

Radiologic Manifestations of patients with TB and DM Conflicting findings ??

• Did not find any difference between DM and non DM cases

• A higher incidence of lower lobe involvement among DM TB cases -- female or age greater than 40 years ?

• No significant difference in the frequency of pleural effusions or isolated pleural TB between patients with and without DM

• Cavitary lesions are more common among diabetic patients -- insulin dependency ?

• A high prevalence of non segmental distribution (30%) and multiple small cavities among diabetic patients.

10

(Parvaneh Baghaei, Majid Marjani, Pedram Javanmard, Payam Tabarsi, Mohammad Reza Masjedi; Diabetes mellitus and tuberculosis facts and controversies, Journal of Diabetes & Metabolic Disorders 2013, 12:58)

Screening for Tuberculosis among patients with Diabetes Mellitus Alur skrining TB pada pasien DM

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• At the TB clinic, the first line recommended test on sputum or other samples is Xpert MTB/RIF in line with current WHO recommendations.

• If the Xpert MTB/RIF assay is unavailable, then investigation by sputum smear microscopy is carried out.

Permenkes 67 tn 2016 tentang Penanggulangan Tuberkulosis

:

Lakukan penegakan diagnosis TB dan tatalaksana sesuai pedoman nasional.

1. Penapisan diulang setiap kunjungan berikutnya.

2. Pemeriksaan foto toraks ulang ditentukan oleh dokter atas indikasi medis.

Jika salah satu

metode penapisan

(gejala atau

rontgen dada)

memberikan hasil POSITIF

Jika kedua metode

penapisan memberik

an hasil NEGATIF

PENCEGAHAN TB PADA PENYANDANG DM

Pencegahan TB pada pasien DM yang tidak sakit TB:

Melibatkan keluarga/pendamping dalam proses edukasi.

Menjaga daya tahan tubuh dengan konsumsi makanan bergizi seimbang dan olahraga secara teratur

Menjaga lingkungan rumah selalu bersih dan sehat, berventilasi baik agar sinar matahari dapat masuk ke dalam rumah

Kendali kadar gula darah

PENCEGAHAN TB PADA PENYANDANG DM

Manfaat pemberian Pengobatan Pencegahan TB (mis. dengan Isoniazid) pada penyandang DM di negara dengan beban TB tinggi belum terbukti dan masih menjadi perdebatan.

Di Indonesia, saat ini pemberian pengobatan pencegahan TB pada

penyandang DM tidak direkomendasikan.

Effect of Tuberculosis on Diabetes Mellitus

• Glucose intolerance has been reported among 16.5% to 49% of patients with active TB.

• “transient hyperglycemia”

• Inflammation caused by cytokines such as IL6 and TNFα in response to TB infection may cause an increase in insulin resistance and decreased insulin production.

• The impairment of blood glucose that occurs with TB and persists for a time during TB treatment is an example of stress-induced hyperglycaemia

(Parvaneh Baghaei, Majid Marjani, Pedram Javanmard, Payam Tabarsi, Mohammad Reza Masjedi; Diabetes mellitus and tuberculosis

facts and controversies, Journal of Diabetes & Metabolic Disorders 2013, 12:58)

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Screening for Diabetes among patients with Tuberculosis

Alur skrining Diabetes pada pasien TB

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Diagnosis DM ditegakkan dengan nilai glukosa plasma dari 2 pemeriksaan yang berbeda waktu:

• Glukosa plasma puasa ≥126mg/dl (puasa adalah kondisi tidak ada asupan kalori minimal 8 jam), atau

• Glukosa plasma sewaktu ≥ 200 mg/dl dengan keluhan klasik (poliuria, polidipsi, polifagi, penurunan berat badan yang tidak dapat dijelaskan sebabnya), atau

• Glukosa plasma sewaktu ≥ 200 mg/dl 2 jam setelah TTGO dengan beban 75 gram. Pemeriksaan glukosa dengan menggunakan metode ensimatik dengan spesimen darah vena.

Jika fasilitas tidak tersedia: gunakan pemeriksaan darah kapiler metode carik kering dengan alat glukometer yang selalu dikalibrasi.

Screening for Diabetes among patients with Tuberculosis

• TB patients who state that they do not have DM should be offered a single RBG measurement at this time to identify those who are at risk and require further investigation with either FPG or HbA1c.

• RBG < 110 mg/dl : The TB patient is at low risk of DM and no further investigation is required.

• RBG ≥ 110 mg/dl : The TB patient requires further investigation---- test (HbA1c) or come back on another day for a FBG test.

• HbA1c ≥ 6.5% : DM .

• FBG ≥ 126 mg/dl: DM .

16 (Union , management of DM-TB a guide to the essential practice, 2018)

Screening for Diabetes among patients with Tuberculosis

• In Indonesia, 61% of diabetics were newly diagnosed concurrent with active TB.

• Risk factors for DM among TB patients :

older age, obesity, inactive lifestyle, and family history of DM.

• Screening : • The sensitivity of 2hPG is reportedly higher than FBS and HbA1c.

• The WHO recommends HbA1c as a diagnostic test for DM.

• When -- at the time of diagnosis of TB and 3months later after initiating treatment.

(Parvaneh Baghaei, Majid Marjani, Pedram Javanmard, Payam Tabarsi, Mohammad Reza Masjedi; Diabetes mellitus and tuberculosis facts and controversies, Journal of Diabetes & Metabolic Disorders 2013, 12:58)

(Union , management of DM-TB a guide to the essential practice, 2018) 17

6.5

7.0

7.5

8.0

8.5

9.0

9.5

10.0

20 30 40 50 60 70

Mo

st R

ece

nt

HA

1C

(%

)

Age of Person with DM at time of TB Screening

Lower Risk

R. Brostrom

Risk Profile for TB Prevention in Persons with DM

Moderate Risk

Higher Risk

The Diabcare-Asia project, a cross-sectional survey of 24,317 diabetic patients from Bangladesh, China, India, Indonesia, Malaysia, Philippines, Singapore, South Korea, Sri Lanka, Taiwan, Thailand, and Vietnam, found that 55% of patients had values of HbA1c exceeding 8% [67]. Poor glycaemic control in Asian populations represents a potentially important risk factor for TB.

The Links Between Tuberculosis and Diabetes

References:

WHO. Tuberculosis and Diabetes Mellitus: Collaborative Framework for Care and Control of Tuberculosis and

Diabetes. Geneva: World Health Organization, 2011.

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Pemeriksaan HbA1c menggunakan metoda High Performance Liquid Chromatographi (HPLC) yang terstandarisasi oleh National Glycohaemoglobin Standarization Program (NGSP). Diagnosis DM ditegakkan jika HbA1c ≥6,5%.

Pemeriksaan HbA1c

Catatan : Saat ini tidak semua laboratorium di Indonesia memenuhi standard NGSP, sehingga harus hati-hati menginterpretasi hasil pemeriksaan HbA1c. Pada kondisi tertentu seperti: anemia, hemoglobinopati, riwayat tranfusi darah 2-3 bulan terakhir, kondisi-kondisi yang mempengaruhi umur eritrosit dan gangguan fungsi ginjal maka HbA1c tidak dapat dipakai sebagai alat diagnostik maupun evaluasi.

Kendali gula darah pada pasien DM dengan TB:

Interaksi antara OAT dan OHO dapat mempengaruhi kadar kedua obat dalam darah efek terapetik sub optimal

Kendali gula darah yang optimal akan meningkatkan outcome pengobatan TB (menghindari non konversi, kegagalan, kematian).

Kepatuhan pasien berkurang jika harus menelan obat dalam jumlah banyak

PENGOBATAN DM PADA PASIEN TB

Terapi INSULIN menjadi

pilihan

PENGOBATAN DM PADA PASIEN TB

Fasilitas Kesehatan

Tingkat Primer

Fasilitas Kesehatan

Rujukan Tingkat Lanjut

Di FKTP, pasien dapat dirujuk untuk memulai terapi insulin.

Bila tidak memungkinkan gunakan OHO.

Pasien yang telah mendapatkan pengobatan satu macam OHO atau kombinasi 2 OHO yang tersedia di FKTP dan pada pemantauan di 3 bulan pertama kadar gula darah tidak terkontrol rujuk ke FKRTL.

Kendali gula darah pada pasien TB dengan DM di FKRTL merujuk pada: PNPK DM, Konsensus pengelolaan dan pencegahan Diabetes

melitus tipe 2 di indonesia tahun 2015, dan PNPK TB

Diabetes and Drug Resistant TB

Deteksi TB RO Pemantauan respon pengobatan secara ketat Uji resistansi (dengan Xpert MTB/RIF atau biakan &

uji kepekaan)

WHO: Diabetes dihubungkan dengan kejadian TB Resistan Obat meskipun bukti masih terbatas.

Indonesia: Temuan Diabetes di antara pasien TB MDR cukup tinggi. RSUP Persahabatan 30-50%, RSUP H Adam Malik 40-60%, RSSA 30-40%

Mekanisme? • Kadar OAT suboptimal karena gangguan absorbsi

atau interaksi obat dengan OHO • Kemungkinan lain? Kepatuhan pengobatan,

kekambuhan, dll

Plasma Consentration of AntiTuberculosis

• TB patients with DM had lower INH and PZA concentrations.

• Negative correlation between blood glucose and drug concentrations suggests delayed absorption/faster elimination of INH and PZA in the presence of elevated glucose.

27

Pharmacology of Drugs in Concomitant Tuberculosis-Diabetes Tuberculosis Affects Anti-diabetes Drugs

IL6 and TNFα as response to TB insulin resistance higher insulin dose

References:

Lancet Infect Dis, 2009; 9(12): 737–746.

Diabetes Affects Anti-tuberculosis Drugs

• Treatment failure among DM (OR 7.65).

• Immunocompromised in DM cavitary disease or delayed sputum clearance extending treatment.

• Plasma rifampicin was twofold lower in DM development of drug resistance.

Decrease in gastric HCl, gastroparesis and impaired absorption

Excess weight gain during TB treatment without dose adjustment

Decreased protein binding of drugs

• Impaired renal function and fatty liver in DM increased risk of drug toxicities.

• DM is a predictor of drug induced liver injury (DILI).

• Diabetic neuropathy worsen isoniazid induced neuropathy, and should receive vitamin B6.

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Pengobatan TB pada Penyandang DM

1.Interaksi dan gangguan metabolisme obat • Kadar rifampisin pada penyandang DM lebih

rendah, dapat menyebabkan dengan gagal pengobatan dan resistansi TB. Kemungkinan mekanisme: • Glukosa↗ meningkatkan pH lambung

menurunkan penyerapan rifampisin • Interaksi Rifampisin dengan OHO

• Rifampisin enzyme-inducer hepar mempercepat metabolisme sulfonilurea dan biguanida kadar OHO dalam darah tidak optimal hiperglikemia

Pengobatan TB pada Penyandang DM

2. Efek samping dan komplikasi

Hepar

OAT dapat menyebabkan drug-induced hepatotoxicity

DM dapat menyebabkan gangguan fungsi hepar, predileksi drug-induced liver injury.

Saraf tepi

Pemberian INH pada pasien DM dengan risiko neuropati perifer dapat disertai vitamin B6

Ginjal

Pemantauan fungsi ginjal pada pasien dengan nefropati diabetikum, sesuaikan dosis Pirazinamid dan Etambutol

Mata

Waspadai retinopati diabetikum, pantau pemberian Etambutol

3.Kepatuhan pasien

Pengawas Menelan Obat (PMO) berperan untuk memastikan pasien menjalankan pengobatan TB dan DM secara teratur.

Edukasi pasien

Pengobatan TB pada Penyandang DM

4.Pemantauan respon pengobatan

Konversi dahak, kemungkinan gagal dan resistansi obat.

5. Durasi pengobatan TB

Pada pasien TB dan DM dengan kadar glukosa darah tidak terkontrol, pengobatan TB dapat diperpanjang sampai 9 bulan dengan tetap mendasarkan pada mempertimbangkan kondisi klinis pasien.

OAT program TB nasional disediakan untuk lama pengobatan standar 6 bulan. Jika diperlukan, OAT untuk pengobatan setelah 6 bulan dapat diupayakan dari sumber lain sesuai aturan.

6. Evaluasi pasca pengobatan

Waspadai kekambuhan, berikan edukasi bagi pasien agar menerapkan pola hidup sehat.

Treatment

• Pengobatan DM pada TB

• Untuk kendali glukosa darah, pasien TB dengan DM di FKTP, sebaiknya dirujuk ke FKRTL untuk mendapatkan terapi insulin

• Dalam keadaan yang terpaksa pengendalian glukosa di FKTP dilakukan dengan OHO

• Bagi pasien yang mendapat pengobatan tunggal atau kombinasi dan dalam 3 bulan belum mecapai target glukosa, maka pasien dirujuk ke FKRTL

• Untuk kendali glukosa darah pada pasien TB dengn DM di FKRTL merujuk pada PNPK DM (Konsensus Pengelolaan dan Pencegahan Diabetes Melitus tipe-2 di Indonesia, 2015) dan PNPK TB yang sudah ada

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(Juknis Penemuan Pasien TB DM di FKRTL , kemenkes 2015)

Sasaran pengendalian

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Treatment • Metformin is the first-line drug of choice for treating persons with

DM if medication is needed to control elevated glucose levels. • Sulphonylurea derivates can be used as add-ons or in patients who

cannot use metformin although drug-drug interactions with rifampicin limit their use.

• Insulin is effective in patients with severe hyperglycaemia but has several disadvantages limiting its use in TB patients in programmatic settings.

• Insulin may have to be considered if blood glucose levels are very high or in those whose blood glucose levels are not controlled with oral hypoglycaemic drugs.

• People with DM and a history of previous cardiovascular disease should be offered low dose aspirin and a statin.

• Patients with DM and TB need to be counselled about appropriate lifestyle management (smoking cessation, good diet and physical activity).

(Union , management of DM-TB a guide to the essential practice, 2018) 34

• Risiko TB yang lebih tinggi pada pasien dengan DM Tipe 2 dibandingkan tanpa DM Tipe 2 (aHR: 2,01; 95% CI: 1,80-2,25).

• Insiden TB aktif yang lebih rendah pada pasien yang diobati dengan metformin dibandingkan tanpa metformin (aRR: 0,24; 95% CI: 0,18-0,32).

• Pasien dengan kontrol glikemik yang Baik (HbA1c <7%) memiliki resiko TB aktif lebih rendah dibandingkan kontrol glikemik yang buruk (HbA1c> 7%).

• Alisjahbana et al. : peningkatan risiko TB aktif pada pasien dengan glukosa puasa yang buruk (rasio odds (OR): 4,2; 95% CI: 1,5-11,7) dan pasien DM tipe 2 (OR: 4,7; 95% CI: 2,7-8,1).

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Mekanisme metformin sebagai terapi adjuvan pada DM-TB coinfeksi

Other treatment issues with DM

• Gastroparesis

• Vomiting and slow emptying could prevent good drug levels

• Diabetic neuropathy increases risk of INH-related neuropathy

• Baseline assessment of neuropathy

• Vitamin B6 to all diabetics on INH or ethionamide

• Renal insufficiency associated with diabetes

• Adjust dose and dosing interval of EMB & PZA (Cr Cl < 30)

• Increased risk of hepatotoxicity • Multiple medications • Hepatosteatosis

(curry, 2016)

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Treatment

• The standard treatment regimens recommended for drug-susceptible and drug-resistant tuberculosis (TB) remain unchanged with or without Diabetes mellitus (DM).

• Dosages should be given daily throughout both the initial and continuation phases.

• DM is associated with an increased risk of drug-resistant TB (5%) and 0,8% TB only patients and worse TB treatment outcomes, longer time of afb sputum negative (2,5 vs 1,6mo) patients need to be carefully assessed for drug resistance at the start of treatment (using Xpert MT/RIF) and carefully monitored for failure during treatment, higher tx failure (17% vs 2%) and for relapse.

38 (Union , management of DM-TB a guide to the essential practice, 2018; Curry 2016)

4FDC(RHZE)

150/75/400/275

2FDC(RH)

150/150

Treatment The Choice of Anti-diabetic Drugs in TB :

• Insulin : Insulin is not metabolized, it has no pharmacokinetic interactions with RIF or other anti-TB drugs. At the start of TB treatment has been suggested. Some national treatment guideline strongly suggest the use of insulin for DM

• Metformin : Not metabolized by P450 enzymes. RIF increases the expression of organic cation transporter (OCT1) and hepatic uptake of metformin, leading to an enhance glucose-lowering effect. Possible disadvantage is gastrointestinal side effects.

(J Diabetes Metab Disorders, 2012; 11: 28. Chem Biol Interact, 2011; 194: 159-167.)

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Infection controlled • People with both DM and infectious TB

should be treated for at least the first two weeks and preferably the first two months just in the TB clinic and visits to the DM clinic should be avoided wherever possible to prevent the transmission of Mycobacterium tuberculosis to health workers and persons with DM in that setting.

• This may require consultancies from the DM clinic to the TB clinic to assist with complicated cases.

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Recommendations for monitoring

• More frequent lab monitoring

• Baseline and monthly

• Educate symptoms of liver toxicity

• Therapeutic drug monitoring

• Small study showing early TDM for INH and RIF at 2 weeks (n=20) • >60% had subtherapeutic levels

• Dose adjustments led to 88% converting sputum in 2mo

(Heysell SK. Tuberc Res Treat. 2013: 129723)

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Tatalaksana lanjutan setelah diagnosis ditegakkan atau setelah penyulit/komplikasi teratasi atas pertimbangan dokter

RUJUK DAN RUJUK BALIK

Pemeriksaan jika tidak tersedia (foto toraks, Xpert MTB/RIF, biakan dan uji kepekaan TB, glukosa darah vena, TTGO, HbA1c)

Inisiasi pengobatan insulin

Tatalaksana penyulit atau komplikasi

Fasilitas Kesehatan

Tingkat Primer

Fasilitas Kesehatan

Rujukan Tingkat Lanjut

Conclusion

1

2

3

4

The association between diabetes and tuberculosis

is the next challenge for global tuberculosis control

In people with TB, it may be appropriate to actively

screen for DM and vice versa

Improved understanding of the bidirectional

relationship of the two diseases is necessary

Prevention, screening, and treatment also monitoring

of both diseases together is more effective.

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TERIMAKASIH

44

Guideline ADA 2018

Guideline ADA 2018

PERKENI 2015

Obat Anti diabetic

Efikasi dan Side effect OAD

Penggolongan insulin