|Year : 2019 | Volume
| Issue : 3 | Page : 305-308
Multidrug resistance as a cause of steroid-nonresponsive downgrading type I reaction in Hansen's disease
Surabhi Sinha1, Kabir Sardana1, Diksha Agrawal1, Purnima Malhotra2, Mallika Lavania3, Madhvi Ahuja3
1 Department of Dermatology, STD and Leprosy, Dr. RML Hospital and PGIMER, New Delhi, India
2 Department of Pathology, Dr. RML Hospital and PGIMER, New Delhi, India
3 Department of Molecular Biology, Stanley Browne Laboratory, TLM Community Hospital, New Delhi, India
|Date of Web Publication||12-Sep-2019|
Dr Kabir Sardana
Room 108, OPD Building, Dr. Ram Manohar Lohia Hospital and PGIMER, Baba Kharak Singh Marg, New Delhi - 110 001
Source of Support: None, Conflict of Interest: None
While Type 1 reaction in Hansen's disease is commonly encountered, the triggers and reasons for its persistence are not well understood even though the immunological milieu and cytokine interplay have been studied. Herein, we present a case of Type 1 downgrading reaction in which multidrug resistance was the probable cause of steroid-nonresponsiveness and which responded promptly on starting alternate antileprosy treatment.
Keywords: Downgrading reaction, leprosy, resistance, type 1 reaction
|How to cite this article:|
Sinha S, Sardana K, Agrawal D, Malhotra P, Lavania M, Ahuja M. Multidrug resistance as a cause of steroid-nonresponsive downgrading type I reaction in Hansen's disease. Int J Mycobacteriol 2019;8:305-8
|How to cite this URL:|
Sinha S, Sardana K, Agrawal D, Malhotra P, Lavania M, Ahuja M. Multidrug resistance as a cause of steroid-nonresponsive downgrading type I reaction in Hansen's disease. Int J Mycobacteriol [serial online] 2019 [cited 2020 Jan 24];8:305-8. Available from: http://www.ijmyco.org/text.asp?2019/8/3/305/266492
| Introduction|| |
Leprosy Type 1 reactions have been typified by the term reversal reaction which signifies the sole presence of an upgrading type which is not correct as downgrading reactions are often seen. While numerous triggers have been described the antigenic expression of viable M leprae has been given less attention. Signficantly resistance as a cause of downgrading reaction has never been reported. Our case confirms the role of resistance in downgrading reaction with a clinical correlation where the modified leprosy treatment resulted in sustained clinical improvement.
| Case Report|| |
A 38-year-old Indian female presented to the dermatology outpatient department with an acute eruption of multiple painless persistent red raised lesions over her body for the past 15 days. The lesions were noted first on the face and quickly encompassed the neck, trunk, and upper and lower limbs with a notable absence of fever or sudden-onset neuritis or weakness of limbs. History revealed that she had noticed two light-colored, slightly numb patches over her left thumb and left leg 2 months ago but had never sought treatment for them.
On examination, multiple erythematous edematous nontender plaques were present predominantly over the face and back, also involving the neck, abdomen, and all four limbs. There were both large and smaller plaques – the fewer larger plaques ranged from 5 cm × 4 cm to 14 cm × 12 cm, whereas the more abundant smaller lesions ranged from 1 cm to 3 cm in diameter. The largest plaque was present on the right side of the back, and few other larger plaques were present on the lower left leg, proximal upper limbs, and buttocks. The larger plaques had an annular configuration with well-defined edges, suggestive of preexisting borderline tuberculoid (BT) plaques that had become edematous and prominent. Most of the new-onset smaller plaques had outward sloping edges, suggestive of new-onset lesions of borderline lepromatous (BL) leprosy [Figure 1]. The palms, soles, flexures, scalp, and mucosae were spared. Well-defined hypoesthetic plaques were present over the left thumb and wrist and the lower left leg. The radial cutaneous nerves and the posterior tibial nerves were bilaterally regularly enlarged and firm but nontender. There was no motor weakness.
|Figure 1: (a) Clinical photograph at admission showing multiple erythematous edematous plaques on the face, (b) Single erythematous plaque with well-defined edges on the back suggesting a borderline tuberculoid plaque with Type 1 reaction, (c) a punched-out lesion (suggestive of BB) and a smaller plaque with outward sloping edges (suggestive of borderline lepromatous), both in reaction|
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Slit-skin smears were made from the edge of one small plaque (BI-4.5), from diametrically opposite edges of the largest plaque (BI-3.4), and from normal looking skin on the earlobes (BI-0). Histopathology of a skin biopsy from a smaller plaque showed perivascular and periadnexal moderately dense lymphohistiocytic inflammatory infiltrate with epithelioid cell granulomas, intragranuloma edema and foamy histiocytes and few foreign-body giant cells, and was Fite stain positive (BI-5), thus compatible with Hansen's disease with borderline Type I reaction [Figure 2] and [Figure 3].
|Figure 2: Moderately dense lymphohistiocytic inflammatory periadnexal and perivascular infiltrate with epithelioid cell granulomas, intragranuloma edema, and foamy histiocytes (H and E, × 400)|
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|Figure 3: Fite stain showing solid-staining and fragmented acid-fast bacilli, Bacillary index-5.0 (Fite, × 1000)|
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The clinicopathological of this patient, not on treatment, with lack of neuritis, the appearance of multiple new lesions of the lepromatous pole and histological presence of relatively more foamy histiocytes than lymphocytes, confirmed a downgrading Type 1 reaction (T1R).
She was started on Multi constellation bacillary Multidrug therapy (MB-MDT) and oral prednisolone 40 mg once daily in view of the downgrading T1R. As per the departmental protocol (new MB case with BI >2+), we sent a skin biopsy sample to Stanley Browne Research Laboratory, New Delhi, for drug resistance testing. As there was no reduction in erythema or edema after 2 weeks of steroids and new lesions continued to appear, NSAIDs were added to the existing therapy, but the erythema and edema persisted and new lesions continued to appear. The resistance study revealed a “primary” drug resistance to both dapsone and rifampicin. The mutations were at codons S456 L in rpoB gene (rifampicin) and at P55 L in folP1 gene (dapsone) [Figure 4]. She was then initiated on second-line antileprosy treatment (ALT) (minocycline 100 mg, ofloxacin 400 mg, and clofazimine 50 mg – all once daily), and after initiation, there was a significant decrease in edema and erythema of the existing lesions and cessation of appearance of new lesions within the next 2 weeks [Figure 5] and refer [Table 1], for drug and dosage details]. The patient was rapidly tapered to alternate-day prednisolone 20 mg [Figure 6], a dosing schedule which is not usually achieved in Type 1 leprosy reactions. We intend to taper the steroids by 5 mg/fortnight within the next 2 months. Voluntary muscle testing and sensory testing is being repeated monthly and has not shown any decline or signs of reactional activity.
|Figure 4: Chromatogram file showing DNA sequencing analysis of the patient (with mutations highlighted) and control sequences|
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|Figure 5: A significant decrease in erythema and edema in all lesions after 2 weeks of initiation of second-line antileprosy treatment|
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|Figure 6: Clinical photograph at 12 weeks from baseline showing complete resolution of all lesions with postinflammatory hyperpigmentation|
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| Discussion|| |
Ridley and Radia first suggested that T1R can be of different types based on the immunological events taking place during the reaction episode – upgrading, downgrading, and static. Even though upgrading is more commonly seen, this may merely be because upgrading reactions are better documented than downgrading ones; one reason is that patients “under treatment” are more likely to have their progress observed. Apart from clinical findings of new lesions and lack of neuritis or constitutional symptoms, downgrading reactions would have a higher BI as compared to the prereactional histopathology and would have fewer protective cells (lymphocytes, epithelioid cells, and Langhans giant cells) and more foamy histiocytes, suggesting the association with a decline in cell-mediated immunity (CMI). This was seen in our case, and hence, it was a clearly documented case of downgrading reaction.
The possible trigger factors for a T1R are not yet confirmed, and multiple factors have been implicated, which can lead to either a shift to Th1 (commonly) or Th2 cytokine activity. Lately, increased Treg-cells have also been seen to play a role in T1R. Other factors include polymorphisms in TLR2, TNFSF8 gene, and upregulation of pro-inflammatory genes. A unique 44 gene signature, including genes associated with arachidonic acid metabolism, has been identified using PBMC stimulated with Mycobacterium leprae antigen.
Leprosy reactions can have some atypical presentations and may masquerade as or coexist with other infections. Vashisht et al. reported a leprosy patient with a Type 2 reaction who presented with orchitis and neuritis. However, the orchitis did not respond to the treatment for the reaction and was eventually diagnosed to be filarial in origin. Pathania et al. reported a case of histoid Hansen's disease that presented with features of Type 2 reaction, an extremely rare occurrence. Arora et al. reported a patient of BT leprosy with multiple peroneal nerve absecesses with sensorimotor loss as the sole presenting features.
Amongst the various factors implicated in reactions, the role of the bacilli and their secreted antigens is paramount. Opromolla had postulated that the CMI in T1Rs may be related to the multiplication of bacteria and release of their antigens. Recently, Save et al. observed in their study that “viable/metabolically active” M. leprae is an essential component/prerequisite in T1R and the secretory protein Ag85 might be the trigger for T1R. They concluded that the persistence of viable M. leprae and their secreted antigens increases the risk of T1R.
In our case, it can be logically surmised that the prevalent drug-resistant strain would have enhanced the antigenic load of the “viable” bacilli triggering the downgrading T1R. While most of the literature has focussed on steroids, it has been difficult to explain the known and markedly variable response of this in T1Rs. The salutary response in our case with concomitant ALT corroborates with the action of ALT on resistant bacilli. While the total duration of prednisolone treatment is 6–20 months for BL patients with T1R, the rapid response and tapering of steroids in our case was probably possible due to the action of ofloxacin and minocycline, wherein daily doses of ofloxacin kills >99% of the viable organisms within 22 days with a similar bactericidal activity of minocycline).,,, Thus, our case is representative of a hitherto unreported finding of drug resistance as a possible cause of downgrading T1R. Ideally, a mouse foot-pad inoculation is ideal to confirm the resistance, but the delay in results can hamper the emergent therapeutic intervention needed in such a case. However, we believe further investigations along these lines might possibly expand the focus of therapy of type 1 reactions beyond steroids.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]