Consensus?
• Treat active TB after renal transplantation
with the same therapy as general
population (Evidence level B)
• If rifampin is used, monitor blood levels of
calcineurin inhibitors and rapamycin. Use
rifabutin as an alternative (Evidence
level C)
Risk factors for Post-TxTB
• DM
• Chronic liver disease
• Cyclosporine therapy
Case series
• Mycobacterial infection in 1261 renal
transplant pts
• 27pts (2.1%) developed infection (20 had
M. Tb)
• Mean age 40 years old with mean time of
immunosuppression=26 months
• Immunosuppression was continued in all
cases and doses were adjusted according
to levels
• TB dissemination rates – 1% in general
population vs 35% in post Tx pts.
• No difference with cyclosporine vs
“conventional therapy”. However, risk is
higher with the use of OKT3 (anti-CD3
monoclonal antibody)
• From another study, TAC or MMF were
associated with development of TB earlier
and in younger patients
Vitamin D: A New Old Cure for TB?
Alexander Usorov, MD
9-18-07
Overview
• Is TB that big of a deal?
• What do the observational studies show?
• What are the mechanisms of action?
TB – a big deal?
• Global emergency
• M. Tb. Kiils a human being every 15
seconds
• 8.8 million new cases in 2003
• 1.7 million deaths
• 1/3 of World’s population is infected with
M. tubecrulosis
• Leading cause of death in women of
reproductive age and HIV pts
• In the US, 10-15 milllion ppl are infected
• Leading cause of death in AIDS pts
• Higher prevalence of XDR TB in AIDS pts
Observations
• 1903 – Niels Ryberg Finsen wins Nobel prize for
demonstrating that UV light treats pts with lupus
vulgaris (cutaneous form of TB)
• 1905 – Robert Koch wins Nobel prize for
isolating tubercle bacilli (which he did in 1882)
• 1854 – Hermann Brehmer opens first ever
sanatorium (himself suffered from TB)
• 1887 – Edward Livingston Trudeau opens first
sanatorium in the United States (Saranac Lake,
NY) after observing that rabbits infected with TB
had a more severe course if kept indoors in the
dark.
Selman Waksman discovered Streptomyces griseus.
Streptomycin was used successfully in 1944, which led to
Nobel Prize in 1952
1946 –pts with lupus vulgaris were treated with Vitamin D2 and 18 out
of 32 were cured (Dowling et al in Lancet 1947: 919-922)
Celiac Disease and TB
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•
•
•
•
•
Pts with celiac disease were found to have higher risk of TB, HR 3.74
(Ludvigsson et al. Thorax 2007;62:23-28)
Follow up to a study by Williams et al (Susceptibility to TB in patients with
celiac disease. Tubercle 1988;69:267-74) where positive relationship was
established and showed a sixfold increase in death from Tb among CD
patients.
Swedish registery compared 14,335 pts with celiac disease to 69,888
mached individuals in a general population
Impressive ability to collect medical data as a result of Swedish National InPatient Register
Only 24 pts in CD group developed TB, compared with 35 pts in general
cohort
Most likely due to malabsorption and lack of Vitamin D in pts with CD
Vitamin D and TB immunity
•
•
A single dose of Vit D enhances immunity to Mycobacteria ( Martineau et
al. Am J Respir Crit Care Med 176;208-213, 2007)
Double-blind RCT in 192 healthy adult TB contacts in London
– Single oral dose of 2.5mg Vit D vs placebo
– Measured response to BCG-lux (measures the ability of whole blood to restrict
the growth of recombinant reporter mycobacteria in vitro)
– Single dose of Vit D significantly enhances TB pts’ antimycobacterial immunity in
vitro
– Profound Vit D deficiency in 40% of cohort; independently associated with South
Asian and African-Americans ( may be the effect of increased skin pigmentation
in reducing cutaneous Vit D synthesis)
Vitamin D supplementation and sputum
conversion
• Indonesian study in 2006
• Double-blind RCT, Vit D vs placebo (in addition to RIPE)
in 67 pts with active pulmonary TB
• Rate of sputum conversion as follows
– Vit D 100% Placebo 76% (p=0.002)
• More subjects with radiologic improvement in Vit D group
How does it all work?
• 1986-1987 Rook and Crowle infected human monocytes
and macrophages with M. Tb. and added 1,25D3, which
triggered significant antimicrobial activity
• Subsequently, Toll-like receptors were discovered.
• TLRs are pattern-recognition receptors whose activation
induces expression of antimicrobial peptides
• 11 subtypes of TLRs are expressed on various types of
immune and non-immune cells
• TLRs trigger direct antimicrobial activity against
intracellular bacteria as well as apoptosis, cytokine
secretion, and so on
• TLR2-TLR1, TLR4 and 5, TLR2-6 respond
to ligands of bacterial origin
• TLR3, TLR 7, and TLR 8 respond to
ligands of viral origin (targets of imiquimod
and resisquimod for txt of genital warts
and herpes)
• TLR 9 – to both
• TLR4 – possible role against fungal
organisms
Human TLRs and their ligands. TLR 2 heterodimerizes with TLR1 and TLR6 to recognize triacyl- and diacyl-lipopeptides. TLR4
and TLR5 ligands are LPS and flagellin, respectively. These TLRs are supposed to recognize products derived from bacteria. By
contrast, TLR3 recognizes viral dsRNA, whereas TLR8 recognizes viral ssRNA. TLR9 recognizes DNA from both bacteria and
viruses. TLR7 and TLR10 have no known natural ligand; however, TLR7 can be stimulated by synthetic compounds such as
imiquimod. TLR signaling is mediated via two different adapters, MyD88 and TRIF, which lead to activation of NF-κB and IRF3,
respectively. MyD88 interacts directly with TLR5, TLR7, TLR8 and TLR9. TLR2–TLR1, TLR2–TLR6 and TLR4 associate with
MyD88 through TIRAP; it is unclear how MyD88 associates with TLR10. TRIF directly associates with TLR3, but requires TRAM
to interact with TLR4.
Upregulation of macrophage 1α,25(OH)2D synthesis following administration of pharmacologic doses of vitamin D in active
Mycobacterium tuberculosis infection. In the granuloma both IFNγ and ligation of macrophage TLR2/1 by M. tuberculosis induces
macrophage expression of 25(OH)D-1α-hydroxylase. Administration of pharmacologic doses of vitamin D results in increased
circulating concentrations of free 25(OH)D, which is metabolised by upregulated 1α-hydroxylase to 1α,25(OH)2D. This may either
act in a paracrine manner to modulate immune responses in the granuloma, or, if produced at high concentration, may enter the
systemic circulation and induce hypercalcemia.
• DEFENSINs
– Antimicrobial peptides produced by activation of TLR
– 3 major classes : alfa-defensins, beta-defensins,
cathelicidins
• Alfa – predominantly in neutrophil granules
• Beta – epithelial cells of airways and intestines
• Cathelicidins – almost everywhere
Human TLR2–TLR1-induced antimicrobial mechanism against intracellular mycobacteria. TLR2–TLR1 stimulation results in the
upregulation of the expression of Cyp27B1 and of VDR. Cyp27B1 converts inactive vitamin D (25D3) into its active form (1,25D3).
The intracellular pool of 25D3 is shuttled into the cell via the vitamin D binding protein (DBP). Once activated, 1,25D3 can then bind
to and activate the VDR, and induce transcription of antimicrobial factors, including the antimicrobial peptide cathelicidin
(Cath.). The cathelicidin peptide can then traffic into intracellular compartments harboring mycobacteria. Whether or not cathelicidin
has a role in the TLR-induced antimicrobial activity is still unclear. However, the cathelicidin peptide has been demonstrated to kill
Mycobacterium tuberculosis directly. Therefore, cathelicidin probably has an important role in the TLR2–TLR1-mediated
antimicrobial activity, but is probably not the only effector. The induction of host-defense mechanisms by TLR2–TLR1 depends on
the amount of 25D3 present in the serum. Abbreviation: RIP, rest in peace.
Vitamin D and Transplantation
• Possible role of Vit D in immune tolerance, when its
deficiency causes failure of tolerance mechanisms
leading to autoreactive cytotoxic T-cell activation
• Several reports of acceleration of allograft rejection and
induction of autoimmune diseases in transplant pts with
low levels of Vit D
• Nonhypercalcemic Vit D receptor agonist BXL-628 (as
well as calcitriol) inhibits, as a monotherapy, acute and
chronic graft rejection in mouse models. (Transplantation
80:81-87)