Showing posts with label Immunology. Show all posts
Showing posts with label Immunology. Show all posts

Tuesday, March 26, 2013

Difference between Jopling’s downgrading and upgrading reactions.


Leprosy Mailing List – April 29th, 2012
Ref.:   Difference between Jopling’s downgrading and upgrading reactions.
FromJ A. Barreto, S Paulo, Brazil


Dear Dr Noto,

Many thanks for circulating our clinical case of about “Borderline leprosy in reaction in a boy from Brazil” (LML March 24th, 2012).  Herewith I would like to comment on the difference between Jopling’s downgrading reaction and upgrading reaction.

Initially, the most important feature is the presence of viable (“solid” or globi) bacilli.  In downgrading reaction, there are viable bacilli, despite the presence of a granulomatous epithelioid reaction; which is seen on the tuberculoid side of the leprosy spectrum.  Actually a “granulomatous epithelioid reaction” can be found on the following three distinct conditions: 

First condition
True TT leprosy (rare).  In this case, bacilloscopy in biopsy specimens ranges from 0 to 1+, and bacilli are usually found, when present, inside dermal nerve branches.

Second condition
BT leprosy (most common).  In this case, bacilloscopy in biopsy is positive, usually 2+ or 3+, inside dermal nerve branches, macrophages (less common), sub-epidermal area and smooth muscle of hair follicles.

Third condition
Type 1 reaction.  Borderline tuberculoid (BT) and mid borderline (BB) leprosy can show epithelioid cells, which in turn means that macrophage differentiation and antigen processing was done, due to IL2 plus IFN-gamma and TNF alfa functions.  What does it mean the presence of epithelioid cells together with viable (solid or globi) bacilli?  This is easy to understand: it means that the macrophage differentiation was not proper and bacilli are still multiplying.  This pattern is typical of the non-treated borderline group, where cellular immunity is partial, and is the reason why most BT patients downgrade to borderline lepromatous (BL), progressively or during reactions.  According to Ridley, indeed, most of BL patients results from downgraded BT.

Coming back to the clinical case we presented; the boy had globi under the epidermis, and it means that this is a downgrading reaction.  Upgrading reaction will never show globi, that is to say aggregations of viable (solid or well stained) bacilli.  This boy also did not receive antibiotics.  Clinicians in the past had already noticed that downgraded reaction occurred in untreated borderline patients [B Naafs personal communication]. 

Unfortunately, leprosy knowledge has been lost since the Ridley and Jopling (R&J) Classification was forgotten, and a new classification (W.H.O.) based only on the number of lesions is nowadays the rule. 

Best regards,

Jaison A. Barreto
Dermatologist and Dermatopathologist

More details can be found on the suggested bibliography.
(Ridley DS. Skin biopsy on leprosy. 2ed. 1987 and Hastings RC. Leprosy 2ed. 1994)

Downgrading and upgrading type 1 reactions. Do they exist?


Leprosy Mailing List – April 26th, 2012
Ref.:   Downgrading and upgrading type 1 reactions.  Do they exist?
FromA Bryceson, London, UK



Dear Salvatore,

I refer to Prof. Kar’s message << Downgrading type 1 reaction? >> [LML April 10th, 2012]

The problem in understanding type 1 reactions lies with the nomenclature, not the immunology.  Cell mediated immunity is the process that, if all goes well, controls the leprosy infection.  More cell mediated immunity (CMI) results in upgrading and increased control; less CMI results in downgrading and decreased control.

I think of a type 1 reaction as a hypersensitivity reaction between antigen and specifically sensitized lymphocytes.  Imagine the patient, or a nerve, to be a test tube containing antigen and lymphocytes.  Add more lymphocytes (as in upgrading) and the reaction, as measured by titrated thymidine incorporation, increases.  Add more antigen (as in downgrading) and the reaction increases.  Thus it is possible to have a type 1 reaction associated with upgrading and a type 1 reaction associated with downgrading.

Clinically, the reactions are indistinguishable.  The history, clinical examination and bacillary index indicate whether the underlying disease is upgrading or downgrading, and thus the prognosis.  If downgrading continues (the patient does not receive anti-leprosy treatment) the infection is uncontrolled and the concentration of antigen in the test tube continues to rise and will eventually suppress the reaction.

We might have a clearer understanding of reactions associated with shift along the borderline tuberculoid (BT) – borderline lepromatous (BL) spectrum if we were to replace the terms upgrading reactions and downgrading reactions with the terms type 1 reaction associated with upgrading, and type 1 reaction associated with downgrading.

With best wishes,

Anthony

Wednesday, February 29, 2012

Heiser Program for Research in Leprosy


Leprosy Mailing List – January 12th, 2012
Ref.:    Heiser Program for Research in Leprosy
From:  P Brennan, Colorado, U.S.A.  


Dear Salvatore,
I would be very grateful if you would announce the 2012 Request for Proposals from the Heiser Program (attached).  Full details and access to application forms are on The New York Community Trust  website (nycommunitytrust.org); it is in the Grant making section under Requests for Proposals, Heiser.  The deadline for applications is March 20, 2012. The major difference in 2012 is that the Heiser Program is funding only leprosy research and will not support postdoctoral fellowships in tuberculosis research.
Thank you,
Patrick Brennan on behalf of: 
Len McNally, Director,
The Heiser Program for Research in Leprosy, The New York Community Trust,
909 Third Avenue, New York, New York 10022, U.S.A.  
Tel: (212) 686-0010, ext. 556; FAX: (212) 532-8528; e-mail: lm(at)nyct-cfi.org

Wednesday, November 16, 2011

Early diagnosis and treatment is the key in the fight against leprosy


Leprosy Mailing List – November 13th, 2011 
Ref.:   Early diagnosis and treatment is the key in the fight against leprosy.
From: H K Kar, New Delhi, India

Dear Dr Noto,
Thank you very much for circulating Dr Saunderson’s message and the Final Report of the “Leprosy Vaccine Summit” (LML Nov. 08th, 2011). 
Rethinking of leprosy vaccine research is a positive approach in the direction of leprosy eradication from the globe.  It should be cost effective even for vaccination of contacts.  In India we were all involved in vaccine trial using various atypical mycobacterial antigens like Mw, ICRC, BCG etc. in last three decades with some success.  However, it could not be implemented in the field due to lack of cost effectiveness.  Chemoprophylaxis has shown some success.  Ultimately it is the early diagnosis and treatment, the key to eradication.
Regards,

Dr (Prof.) H K Kar
Consultant & HOD
Department of Dermatology, STD & Leprosy
P.G.I.M.E.R. and Dr Ram Manohar Lohia Hospital
Baba Kharag Singh Marg
New Delhi-110001

What is in paucibacillary (PB) leprosy?


Leprosy Mailing List – November 12th, 2011
Ref.:   What is in paucibacillary (PB) leprosy? From: J Barreto, Bauru, S. Paulo, Brazil

Dear Dr Noto,
Thank you very much to my friend Dr Ben Naafs, and also to Dr Pieter Schreuder for their comments (please see LML 9th Sept., 2011).
1. Yes, there is a spectrum in leprosy classification, and low resistant tuberculoid is a fact, even though I have seen only less than 10 cases in more than 10 years, and in more than 15.000 slides of leprosy cases which I saw during 8 years as dermatopathologist at the Instituto Lauro de Souza Lima (ILSL).
2. According to 1971 Ridley’s Classification (Five from seven groups), there is a group called TI (Indefinite Tuberculoid), who develops type 1 reaction, but this group is not the same of tuberculoid reactional described by Wade and Lauro de Souza Lima in the beginning of the 20 century.  The name reactional tuberculoid leprosy, grouped later with BT patients in R&J Classification 1962/1966, should be deserved to patients with usually a lesion clinically and histopathologically indeterminate (early), whose developed, in most cases, a reaction in the first or second month of therapy, usually with few or no nerve symptoms, and the normal evolution was to cure.  These patients had a Mitsuda reaction of 2+, i.e., 6 to 10mm diameter, different from TT patients (>10mm or ulcerated).  Ridley, in his paper "Skin biopsy on Leprosy", 1987, second edition, pointed that TI is not the same as TR, though both undergone reactions.  At the ILSL we recognize 2 groups of low resistant tuberculoids: "T in reaction", which in turn are really BT patients, i.e., annular tuberculoid lesions with satellite lesions and erythema after the beginning of treatment, and "reactional tuberculoid", described above.
3. It is also important to know that is very difficult to distinguish, even histopathologically, true TT from BT cases.  Dr Fleury published a paper about this, in Hansenologia Internationalis.  Ridley (1974) pointed some clues, as the lower destruction of epidermis and dermal nerve branches, as well as the presence of more Langhans giant cells in granuloma, but the main clue is the bacilloscopy (slit-skin smear examination), and sometimes only the evolution over long term follow up.
4. About bacilloscopy, as many as 90% of smears are made with bad quality in Brazil, and I believe that few technicians in the world, as well, are able to perform it correctly.  I performed a study in 2010, in the state of Mato Grosso do Sul, Brazil, that I am going to present on the next International Leprosy Congress in Brazil.  Why I made a study in this state? Because the quality of smears, on indirect evaluation, was said more than 99% good, and for this reason, it was the model for the country.  Nevertheless, when we went to the field, and on direct evaluation, less than 10% of the smears were made in good conditions, i.e. good collection, fixation, staining and reading.  This is the likely reason which explains why patients with less than 5 lesions are said PB: the smear collection from the lesions needs a good technics, and usually it is not possible to make it with tools other than the fingers, and for this reason almost all technicians DO NOT COLLECT from lesions.  This is a fact.  Once in cases of initial borderline leprosy the bacilli are found only in lesions, of course, index points will show no bacilli, and patients will be considered wrongly PB.
5. How long must we wait to say the patient is healed?  5yrs?  10yrs?  How many long term follow up of PB patients, with good methodology, are described on literature?  On my recent review of literature for my PhD thesis, ALL of them had less than 10yrs, and ALL the relapsed cases in these studies were diagnosed only by spontaneous demand.  If we wonder that M. leprae can stay dormant in Schwann cells as many as 10yrs, and duplication time is almost 2 weeks, how many time must we wait to find and show viable bacilli on skin biopsies, or even on smears (which have lower accuracy), in order to distinguish between reversal reaction and relapse, after a short course of treatment in a borderline patient?
6. Finally, if, in a normal distribution of cases in the spectrum, only 10% have Mitsuda reaction positive (Ridley, 1974), and only these patients are able to destroy dormant bacilli inside nerve fibers, once metabolic inactive M. leprae will not be destroyed by MDT, what will be the real percentage of good prognosis MDT PB treated patients?
These are only some questions, which I still do not have answers.
Regards,
Jaison

Indian Council of Medical Research (ICMR) calls for proposals to evaluate Leprosy Eradication Programme


Leprosy Mailing List – November 8th, 2011 
Ref.:   Indian Council of Medical Research (ICMR) calls for proposals to evaluate Leprosy Eradication Programme
From: S. R. Narahari, Kasaragod, Kerala, India

Dear Dr Noto,
Can you please circulate the enclosed “ICMR Proposal”?  I think many leprosy mailing list readers might be interested.
ICMR calls for proposals to evaluate Leprosy Eradication Programme
The Indian Council of Medical Research (ICMR) has called for research proposals to evaluate the National Leprosy Eradication Programme (NLEP).  The deadline for scientists and doctors to submit proposals is December 15. 
India achieved leprosy elimination as a public health problem in December 2005, however there are pockets of endemicity where the number of new case detection is still high and the community is at higher risk of being infected with M. leprae.  Over 200 districts of India, in parts of Bihar, Madhya Pradesh, Maharashtra and Tamil Nadu recorded more numbers last year.
Therefore, to address these issues, Secretary, DHR and DG, ICMR has taken steps to promote research by funding projects on the Priority Areas of research in leprosy given below:-
Health Systems Research & Operational Research on integration issues.
.
Studies evaluating current IEC strategies in increasing community awareness.
Studies addressing psychosocial issues for formulation of newer approaches to reduce the stigma, for encouraging early detection and completion of MDT.
Studies for encouraging early detection (through self-reporting) and completion of MDT.
Development of indicators for stigma at community level and evaluation of participation scale for wider use.
.
Nerve Damage and Care of the Disabled at the Community level and impact of field interventions.
Epidemiological studies
.
Estimating trends/prevalence/incidence in India with special emphasis on biological reasons and genetics.
.
Behavioural and social factors influencing the epidemiology of disease.
.
Transmission dynamics of leprosy to identify sources/genotypes, its presence in soil and water and establish chain of transmission in endemic pockets.
.
Study addressing issues related to changing profile of disease.
.
Precise epidemiological data on pooled grade-2 disabilities in rural communities.
.
Leprosy in Children / dynamics of childhood leprosy

Clinical – Research
.
Clinical - Laboratory studies on complications of leprosy and its management.
.
Evaluating effect of newer anti-leprosy drugs/molecules.
.
Studies addressing leprosy relapse and reactions.
.
Detection of early bacteriologically positive Multibacillary Bacillary leprosy and its early management.
.
Use of immunomodulators in relation to leprosy and tuberculosis in children.
.
Use of chemoprophylaxis in household contacts.

Operational Research.
Effect of inclusion of leprosy in a community based integrated rehabilitation disability care programme.
.
Research on disability prevention and identification of predictors of early nerve damage in leprosy.
.
Varying distribution pattern of patients with nerve damage, acute, chronic or "silent".
.
Identification of pre-clinical disease markers like nerve conduction tests etc.

Basic Research
.
Studies using genomics, proteomics and other approaches to understand the host-parasite interaction and pathogenesis of the disease.

Basic Immunology
.
Translational research including newer technology such for detection of M. leprae from environment.
.
Tools to identify leprosy susceptibility
Drug resistance studies
.
Resistance to anti-leprosy drugs.
.
Studies on use of second line newer drugs for resistant and relapse cases.
Surgical aspects
.
Trials on immediate post-operative active mobilization of hand following deformity correction and to investigate if the benefits of tendon transfers can be improved with early mobilization.
.
Effects of early mobilization to reduce dependence on therapist to attain a satisfactory result.
.
Investigation of economic and social impact of this technique in varied patient groups.
.
Trials regarding the safety of immediate active mobilization protocol (IAMP) to other tendon transfers.
.
Assessment of economic impact of earlier return to work by RCS patients and also the cost of care.
.
Understanding the neurobiology of tendon transfer rehabilitation.
.
Standard of ulcer care in leprosy
Concept proposals (limited to 5 pages) are invited from scientists of various recognized Research Institutions, Universities, Medical Colleges etc. in India. The concept proposals should include the following details.
1) Title of the concept
2) Name, address, telephone number including the mobile no. and e-mail ID of PI & Co-PI
3) Participating Institutions
4) Need for the study
5) Type of study: Hospital based (clinical), Field based (epidemiological), Lab. Based (Basic)
6) Major objectives and milestones
7) Research focus, short term goals, long term goals and scientific strategies to achieve this
8) Research Plan: Including sample size statistically calculated, place and methods of collection of samples, detailed methodology, etc.
9) Expected deliverables/Outcomes
10) Relevance/Applicability in the national interest.
11) The main strength(s) which merit(s) this support should be described in less than 200 words.
12) A brief biodata of PI and Co-PI (along with proof of expertise in form of publications).

After review the investigators of the selected proposals would be invited to submit the full proposals.  The concept proposal (one electronic copy and 15 hard copies) is to be sent on or before December 15th 2011.  The project proposals may be sent to, `
Dr. Manjula Singh,
Scientist `C',
Division of ECD,
ICMR, V. Ramalingaswami Bhawan, New Delhi 110-029



Best regards,
Dr. S. R. Narahari MD; DVD (dermatology)
Director
Institute of Applied Dermatology
6/1665, Nayaks Road, Kasaragod, Kerala, India
Phone: +91-4994-223687 & 230116; Res +914994223625
www.iad.org.in

Wednesday, November 9, 2011

Relapse in paucibacillary (PB) leprosy


Leprosy Mailing List – October 16th, 2011 
Ref.:   Relapse in paucibacillary (PB) leprosy
From: S Noto, Genoa, Italy

Dear Jaison,
Thank you very much for your message (LML Oct. 15th, 2011 - “What is paucibacillary (PB) leprosy?)  Kindly, see in attachment the pictures of a case from Genoa.  The young patient was treated as paucibacillary leprosy in Senegal.  Then he migrated and in Italy he relapsed.  The slit-skin smear examination was negative; actually we found 1 (one) fragmented bacillus.
Best regards,
S. Noto

What is paucibacillary (PB) leprosy?


Leprosy Mailing List – October 15th, 2011 
Ref.:   What is paucibacillary (PB) leprosy?
From: Barreto J., Bauru, SP, Brazil

Dear Dr Noto
I have seen many cases of "relapsed" borderline tuberculoid patients, 6 to 7 years after discharge by cure, and usually when they were treated as PB leprosy.  I am sending a note to the LML in order to listen to others colleagues opinion.
Regards,
Jaison

WHAT IS PAUCIBACILLARY (PB) LEPROSY? CONSIDERATIONS ABOUT TRUE RELAPSES AND INSUFFICIENT TREATMENT
I don't understand why most borderline tuberculoid (BT) leprosy patients are still located in the same operational classification like polar tuberculoid (TT) patients, i.e., as "PB" leprosy, based only on skin smears.
What is PB leprosy? Since 1962, when Ridley & Jopling defined the spectrum, and in 1971, when Ridley revised and published the "5 of 7 groups Classification" (Ridley, 1972), it became clear that most BT leprosy patients tend to downgrade to BL, and this is the reason why most BL patients arise from downgrading of BT (Ridley, 1987).
Why? Because BT patients are usually Mitsuda negative (less than 5mm of diameter, or 0 to 1+ in Madrid classification); therefore, they clearly differ from Mitsuda positive patients (higher than 5mm of diameter).  This means that they do not develop well defined tuberculoid reaction, that is to say, full epitelioid transformation of macrophages with elimination of antigens (Michalany&Michalany, 1983).
This lack (or gap) of immunity, which differs from TT patients, is the likely reason which explains why the BT patients usually show many bacilli inside dermal nerve branches on Faraco-Fite stain, as well as more false "relapses" (due to insufficient treatment) and, recurrent reactions with neuritis when treated as PB (Nilsen, 1989; Revankar, 1989).
It is also important to say that slit-skin smears are positive only if there are, at least, 10 000 bacilli per gram of tissue (Bang, 2009).  In a 70kg adult, 14 kg (20% of the body weight) are represented by skin. So, in an attempt to find a positive smear, at least bacteriological index (BI) 1+, the patient should have a total load of 140 million of bacilli inside his skin.  This does not seem “few”, i.e., “PB”, in my opinion. 
BT patients may have BI of 1+ to 3+ in biopsy skin slides, this would represent a total skin load ranging from 140 million to 14 billion of bacilli.  It is assumed that at least 1 bacillus, in a million of M. lepraewill be naturally resistant to any single drug of the multi-drug therapy protocol (Hastings, 1998).  So, a total of 140 to 14 000 bacilli should be destroyed every month by the supervised rifampicin, but this drug destroys only metabolically active bacteria.  Once the duplication time of M. leprae is almost 14 days, every month, these dapsone resistant bacilli would have time to duplicate twice, at least.  Therefore, recurrent reactions and neuritis are foreseeable, probably due to continuing replication of bacilli not killed by dapsone during the lag phase (Opromolla, 2000).  There are evidences for this in a few cases.  I personally believe more in the role of autoimmunity. 
Finally, leprosy is a primarily neural disease and, as Schwann cells are bad antigen presenting cells, it is understandable that these patients could have as many as 4+ of bacilli inside nerve trunks which have undergone biopsy, even if the skin smears and biopsy indexes are negative (Barreto, 2007).
Jaison A. Barreto
Dermatologist and Leprologist
Instituto Lauro de Souza Lima
Bauru, SP, Brazil

Wednesday, June 22, 2011

Strain-typing of M. leprae

Leprosy Mailing List – May 31st, 2011
Ref.:   Strain-typing of M. leprae
From: D M Scollard, T P Gillis, J L Krahenbuhl.  Baton Rouge, LA, USA

Dear Salvatore,
We would like to thank Dr. Warren (LML May 16th, 2011) for her interest in the strain-typing of M. leprae that was used in the study published about 3 weeks ago in the New England Journal of Medicine (abstract attached).  This has subsequently been reported in many newspapers around the world and, as she noted, different journalists had somewhat different ideas about this.  If you only read the news accounts it could be confusing. 
As Dr. Warren indicated, for many years it was not possible to identify different strains of M. leprae.  However, as a result of the sequencing of the entire genome ofM. leprae it has become possible, in the last 10 years or so, to identify a small number of differences in the genetic sequences of bacilli isolated from patients in different parts of the world.  This paper marks a major advance in this effort, combining two different molecular techniques to identify small differences in M. leprae DNA.  The result is that we now can, in fact, identify different strains of this organism. 
The investigators used these techniques to examine M. leprae DNA from wild-infected armadillos in the US and compared this with M. leprae DNA from human biopsies.  We found that almost all of the infected armadillos had the same strain ofM. leprae, and a majority of the US patients who had no foreign travel had the same ‘armadillo’ strain.  This indicates that humans and armadillos are sharing this infection, although the exact means of transmission is still unclear.  US patients with a history of foreign travel often had strains of M. leprae associated with other regions of the world. 
There are still many limitations to these strain-typing techniques, but it is clear that we are now at the beginning of an era in which we can use methods like this to ‘track’ different sources of infection with M. leprae, and this is a major advance for epidemiological studies of this disease.  However, determining “strains” by this technique in no way implies a functional difference in the groupings that would result in an altered pathogenic potential, i.e., all strains cause the same range of clinical types of leprosy. 
David M. Scollard, M.D., Ph.D.
Thomas P Gillis, PhD.
James L. Krahenbuhl, Ph.D.

National Hansen's Disease Programs
1770 Physicians Park Dr
Baton Rouge, LA 70816

Mycobacterium leprae

Leprosy Mailing List – May 16th, 2011 
Ref.:   Mycobacterium leprae
From: Grace Warren, Sydney, Australia

Dear Salvatore,
I have seen a number of newspaper articles recently regarding the leprosy bacillus.  It is stated that a new strain of M. leprae has been discovered in the armadillo. As you well know for years we were taught that there was only one strain of M. leprae.  So I write to you to ask that someone give us a summary of the true facts.  Articles in papers and on the web do not always give the practical truth.
One paper says it cannot be passed on to humans.  Another says it can and one article says that in “America some people have one strain and some the other” implying that the armadillo strain can affect humans.  Though another article states it does not.  One article says the two strains are in South America and imply that the armadillo strain is transmitted to humans in S America. 
 I would love to have a bit more true information.  Thank you very much.
Grace Warren
Previously adviser in Leprosy and reconstructive surgery for The Leprosy Mission in Asia (1975-1995)