Saturday, June 22, 2019

(LML) Type 1 reaction: downgrading versus reversal reactions

Leprosy Mailing List – June 22,  2019

Ref.:    (LML) Type 1 reaction: downgrading versus reversal reactions

From:  Ben Naafs, Munnekeburen, the Netherlands


Dear Pieter,


I agree with the remarks by dr Kabir Sardana (LML, June 19, 2019) regarding up- and downgrading reactions. Particular the remark that it may occur in untreated patients. And the damage may be less and easier to treat. Also, a cytokine analyses is worthwhile in my opinion. I agree with Type I upgrading and Type I downgrading as proposed by dr Sardana


Dr Van Hees and myself wrote in an accompanying article (see annex):


"Upgrading and downgrading reactions


In the pre-sulfone era, patients became less bacilliferous or even "cured" after an exacerbation of their leprosy. As a result, they usually suffered from nerve damage. Patients who shifted toward the tuberculoid end of the spectrum were considered to have an upgrading event; had they become more lepromatous, a downgrading event. The original publications mention regression and lepromatous transformation.


When sulfones became available, the occurrence of exacerbations or pseudo exacerbations of the disease after the introduction of treatment was observed, leaving the patients more damaged but with a decreased bacillary load. The term reversal reaction was coined for these phenomena.


Many discarded the concept of a downgrading reaction, because during effective antibacterial treatment, no bacterial multiplication was expected; thus, the term reversal reaction. The concept, however, was never abandoned entirely. Reactions still occurred in untreated and relapsing patients, and some pathologists had the strong impression that when a reaction occurred, they observed the appearance of, or a temporary increase in, the number of M leprae, some of which were solid staining, even in treated patients.


The concept became even more relevant with the introduction of multiple-drug treatment by the WHO. Reactions now did not only occur before treatment and during treatment but also after antimycobacterial treatment. Reactions after treatment became very difficult to discern from a relapse. An increase in the number of solid-staining bacteria could occasionally be observed, only to disappear after the reaction settled. This was explained by assuming that this late reaction had been effective in clearing the bacillary load, thus an upgrading reaction. After the decline in the number of bacilli with effective antimycobacterial treatment, enough of the CMI had been restored to deal with newly multiplying bacteria. Interestingly, the same authors who noticed an increase in bacterial load during a reaction occurring during dapsone monotherapy and during late T1R hardly observed this phenomenon during multidrug treatment.


Initially, to explain the disappearance of bacilli during one type of reaction and not during the other, the concept of protective immunity and nonprotective delayed-type hypersensitivity was introduced. When the reaction was directed against certain antigens, the bacteria were killed. When it was directed against others, there was tissue damage, but no damage to the bacteria. This concept, however, was increasingly challenged. In this respect, discrete T-cell subsets and mycobacterium antigenic determinants appear to control the clinical and immunologic spectrum of leprosy. T cells (probably together with the participation of antigen presenting cells and B cells), within the adaptive immunity, play the pivotal role in both protective immunity and in dictating the pathology.


Another explanation that was proposed is that, during an upgrading reaction, the immunity is directed against antigenic determinants that are essential for the bacterium to survive and that during a downgrading reaction the reaction is directed against antigenic determinants of secreted antigens, remnants of dead and dying bacteria, or even antigenic determinants of the host that the host has in common with M leprae.


A third concept, stating that in both upgrading and downgrading reactions the same antigenic components may be involved, is the most likely one. In this concept, enhanced CMI stimulated by bacterial or human host antigenic determinants competes with a suppressive effect induced by others. The orchestration of the cytokines, which result from these immunologic events, is likely to be responsible for the final effect, upgrading or downgrading. An observation supporting this concept is the finding that different antigenic determinants induce a different cytokine profile in different individuals depending on the genetic makeup and immunologic history of those individuals, including their contact with environmental microorganisms. It should also be realized that events may differ from site to site in the tissues."


Regards,


Ben Naafs 


LML - S Deepak, B Naafs, S Noto and P Schreuder

LML blog link: http://leprosymailinglist.blogspot.it/

Contact: Dr Pieter Schreuder << editorlml@gmail.com


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