Leprosy Mailing List – June 27, 2021
Ref.: (LML) Length of MDT
From: Joel Almeida, London and Mumbai
Dear Pieter and colleagues,
Thanks to Prof. Lockwood for her contribution (LML 24 June 2021, Length of MDT).
However, those views are not entirely available on the facts. In particular, the implication that 20 years of follow-up was available for all patients in a study is incorrect. Patients with as little as one year of follow-up were included in the denominator. This dilutes recurrence/reinfection rates. That is because the typical incubation period of signs of recurrence in LL patients is known to be higher in later years (typically later than five years) than in the first years following the withdrawal of MDT after 12 to 24 months. Diluted estimates and realistic estimates are two different things.
A reasonable solution is to count how many persons were available for follow-up in each year following the withdrawal of MDT. That gives the year-specific denominator of recurrences/reinfections. For example, how many persons were available for follow-up in year 10, and how many of them were first detected to have signs of recurrence in year 10? That gives a reasonably informed estimate of the year-specific recurrence/reinfection rate in year 10 of follow-up. An example of such an analysis is available. The incubation period of signs of recurrence appears to be 6 years or more. The number of patients available for follow-up falls steadily, and very few patients tend to remain available for follow-up in years 15 to 20. For such reasons, estimates of recurrence/reinfection rates tend to be seriously diluted by the inclusion of the first five years of follow-up after the withdrawal of 12 to 24 months of MDT.
More importantly, the ratio of the number of reinfected polar LL patients to newly diagnosed LL patients matters as much as the absolute value of recurrence/reinfection rates. If prevalent neglected polar LL patients with recurrence/reinfection outnumber incident (newly diagnosed) LL patients, then recurrence rates are too high. That is because transmission is maintained largely by accumulated recurrences/reinfections. What is the incidence rate of LL HD (leprosy)? Usually well below 100 in a million, conspicuously less than in TB (tuberculosis). What is the long-term accumulated number of prevalent recurrences among polar LL patients? In the endemic population where I studied reinfections/recurrences in some detail (Karigiri, India), there were over 200 accumulated patients with recurrent high BI (after earlier smear negativity) in a population of about 450,000 persons. That equates to 444 per million accumulated prevalence of patients with recurrence showing high BI. With only 100 per million newly diagnosed LL HD patients and over 400 per million accumulated prevalence of high BI patients showing recurrence/reinfection, transmission is maintained to an important extent by previously treated LL patients.
Transmission happens in otherwise well-run programmes largely because we have been enforcing anti-microbial neglect of anergic patients after 12 months of MDT. Incidentally, the much higher incidence rate of TB makes recurrences relatively less important drivers of transmission in TB than in HD. Therefore analogies between recurrence rates in TB and HD have limited value. The "acceptable" or epidemiologically inconsequential recurrence rate in HD is a fraction of that in TB because the incidence rate of HD is a fraction of that in TB.
Importantly, denial of prolonged anti-microbial protection to high BI patients leads to avoidable ENL (erythema nodosum leprosum) episodes. These can be excruciatingly painful, driving patients to the brink of suicide.
These are the reasons for ensuring prolonged-anti-microbial protection for every high BI patient, preferably after trying immunoprophylaxis with Mycobacterium w (MIP vaccine) in case a particular patient has phenotypic (sub-polar LL) rather than genomic anergy (polar LL).
Further, claims of low recurrence rates among high BI patients tend to be undermined by mixing low (or even zero) BI patients with high BI patients in the analysis. This again dilutes recurrence/reinfection rates. Realistic estimates are quite different from diluted estimates.
Missed or delayed diagnosis of recurrence/reinfection is another source of diluted recurrence/reinfection rates. This happens when an increase in BI at a single site is disregarded. Also when expert clinicians are not available for diagnosing recurrence/reinfection promptly.
Polar LL patients in relatively less endemic areas are predicted and observed to be at lower risk of recurrence than those in more endemic areas. Therefore generalising from low endemic areas to high endemic areas tends to be misleading when it comes to reinfection/recurrence rates among high BI patients.
The trouble with diluted estimates is that bacilli disregard them.
Our choice is not difficult. We could follow the good example of enlightened colleagues in endemic areas who ensure prolonged anti-microbial protection for suspected polar LL patients. These colleagues are confronted by an accumulation of previously treated patients who show subtle signs of recurrence/reinfection. Skin smear microscopy shows acid fast bacilli. If skin smears are omitted or delayed, subtle signs are overlooked and anti-microbial protection is withheld, then neglected patients deteriorate to present with nodules, frank induration, and even ulceration accompanying very painful ENL. By contrast, prolonged anti-microbial protection reduces recurrence/reinfection as well as ENL and transmission.
There are options for prolonged anti-microbial protection of high BI patients in endemic areas. For destitute polar LL patients who rely on free-of-charge treatment, MDT continued beyond 12 months can suffice. For patients who can afford to pay, immunoprophylaxis with MIP can be followed by post-MDT chemoprophylaxis with a combination of bactericidal drugs.
The alternative would be anti-microbial neglect of polar LL patients. The consequences would be severe, for the patients (including excruciatingly painful ENL) as well as the population of endemic areas (by continued transmission). Some countries experience persistently high transmission rates largely because they withhold prolonged anti-microbial protection from polar LL patients. This undermines their otherwise excellent programmes. It seems wiser to protect polar LL patients against reinfection in endemic areas, and so reduce transmission. This was the secret of success in Karigiri and Shandong. It can open the door to success in every endemic area.
Joel Almeida
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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