Mycobacterium leprae: Difference between revisions

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Mycobacterium leprae
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βˆ’
== Background ==
 +
==Background==
βˆ’
=== Microbiology ===
 +
===Microbiology===
βˆ’
* Slow-growing [[Stain::Gram-positive]] and [[Stain::acid-fast]] [[Cellular shape::bacillus]]
  
   
  +
*Slow-growing [[Stain::Gram-positive]] and [[Stain::acid-fast]] [[Shape::bacillus]]
βˆ’
=== Epidemiology ===
  
βˆ’
* About 1 million cases worldwide each year, but is rare in North America
  
βˆ’
** Number may be underestimated due to difficulties with reliable diagnosis
  
βˆ’
* Most commonly occurs in Southeast Asia (especially India) and Brazil
  
βˆ’
* Decreasing incidence over the past several decades, likely due to short-course multidrug therapy starting in 1982
  
βˆ’
* Humans are thought to be the main reservoir, but it has been found in animals as well (particularly nine-banded armadillos)
  
βˆ’
* Transmitted most likely by respiratory droplets, though can also be transmitted by direct contact, transplacentally, through breast milk, and after animal exposure
  
   
βˆ’
=== Risk Factors ===
 +
===Epidemiology===
βˆ’
* Age, with peaks in adolescence and β‰₯30 years
  
βˆ’
* Adult men (compared to adult women)
  
βˆ’
* Duration of contact with an infected patient, and the burden of bacilli in the patient
  
   
  +
*About 1 million cases worldwide each year, but is rare in North America
βˆ’
=== Pathophysiology ===
  
  +
**Number may be underestimated due to difficulties with reliable diagnosis
βˆ’
* The clinical spectrum of disease depends on the host immune response to infection
  
  +
*Most commonly occurs in Southeast Asia (especially India) and Brazil
βˆ’
* A robust Th1 CD4 response causes tuberculoid leprosy, which is paucibacillary and well-controlled
  
  +
*Decreasing incidence over the past several decades, likely due to short-course multidrug therapy starting in 1982
βˆ’
** Requires interferon-Ξ³
  
  +
*Humans are thought to be the main reservoir, but it has been found in animals as well (particularly nine-banded armadillos)
βˆ’
* A Th2 CD4 response causes lepromatous leprosy, which is multibacillary and more progressive
  
  +
*Transmitted most likely by respiratory droplets, though can also be transmitted by direct contact, transplacentally, through breast milk, and after animal exposure
   
  +
===Risk Factors===
βˆ’
== Clinical Manifestations ==
  
βˆ’
* Following exposure, about 95% clear it spontaneously
  
βˆ’
* For those who do not, there is an incubation period of [[Usual incubation period::3-5 years]] (with [[Incubation period range::wide range]]) that is usually followed by indeterminate leprosy
  
βˆ’
** Single, ill-defined, hypopigmented skin lesion
  
βˆ’
** About 75% spontaneously resolve, with the other 25% progressing
  
βˆ’
* Classic presentation is anaesthetic hypopigmented skin lesion with thickened nerves
  
βˆ’
* Skin lesions can be: annular, asymmetric macules or plaques with central clearing and elevated borders (in tuberculoid) or symmetric, poorly-demarcated nodules and plaques or diffuse infiltration (lepromatous)
  
βˆ’
** Lepromatous can also have xanthoma-likek or dermatofibroma-like lesions, leonine facies, and eyebrow alopecia
  
   
  +
*Age, with peaks in adolescence and β‰₯30 years
βˆ’
=== Spectrum of disease ===
  
  +
*Adult men (compared to adult women)
βˆ’
* Clinical spectrum can be classified based on the number of lesions and burden of mycobacteria
  
  +
*Duration of contact with an infected patient, and the burden of bacilli in the patient
βˆ’
** '''Paucibacillary (PB)''' disease has 1 to 5 skin lesions, without bacilli on skin slit smear
  
βˆ’
** '''Multibacillary (MB)''' disease has more than 5 skin lesions, with or without nerve involvement or bacilli on slit-skin smear (regardless of number of lesions)
  
βˆ’
* Can also be classified based on general clinical appearance
  
βˆ’
** '''Tuberculoid leprosy (TT)''' corresponds to paucibacillary
  
βˆ’
** '''Borderline tuberculoid leprosy (BT)'''
  
βˆ’
** '''Borderline leprosy (BB)'''
  
βˆ’
** '''Borerdline lepromatous leprosy (BL)'''
  
βˆ’
** '''Lepromatous leprosy (LL)''' corresponding to multibacillary disease
  
   
βˆ’
=== Type I reaction ===
 +
===Pathophysiology===
βˆ’
* A cell-mediated hypersensitivity reaction that can develop in the course of treatment
  
βˆ’
* Also known as a '''reversal reaction''' due to the apparent worsening of the lesion
  
βˆ’
* Occurs most commonly in the borderline cases and may signal progression to the cell-mediated tuberculoid end of the clinical spectrum
  
   
  +
*The clinical spectrum of disease depends on the host immune response to infection
βˆ’
=== Type 2 reaction ===
  
  +
*A robust Th1 CD4 response causes tuberculoid leprosy, which is paucibacillary and well-controlled
βˆ’
* A humorally-mediated hypersensitivity reaction that can develop in the course of treatment
  
  +
**Requires interferon-Ξ³
βˆ’
* Also known as '''erythema nodosum leprosum'''
  
  +
*A Th2 CD4 response causes lepromatous leprosy, which is multibacillary and more progressive
βˆ’
* Characterized by systemic illness and immune-complex deposition that appears as groups of tender subcutaneous nodules
  
βˆ’
* May have other signs of vasculitis, including fevers, arthralgias, neuralgia, lymphadenopathy, orchitis, and dactylitis
  
   
  +
==Clinical Manifestations==
βˆ’
=== Physical examination ===
  
  +
βˆ’
==== Commonly affected nerves ====
  
  +
*Following exposure, about 95% clear it spontaneously
  +
*For those who do not, there is an incubation period of [[Usual incubation period::3-5 years]] (with [[Incubation period range::wide range]]) that is usually followed by indeterminate leprosy
  +
**Single, ill-defined, hypopigmented skin lesion
  +
**About 75% spontaneously resolve, with the other 25% progressing
  +
*Classic presentation is '''anaesthetic''' hypopigmented skin lesion with thickened nerves
  +
*Skin lesions can be: annular, asymmetric macules or plaques with central clearing and elevated borders (in tuberculoid) or symmetric, poorly-demarcated nodules and plaques or diffuse infiltration (lepromatous)
  +
**Lepromatous can also have xanthoma-likek or dermatofibroma-like lesions, leonine facies, and eyebrow alopecia
  +
  +
===Spectrum of Disease===
  +
  +
*Clinical spectrum can be classified based on the number of lesions and burden of mycobacteria
  +
**'''Paucibacillary (PB)''' disease has 1 to 5 skin lesions, without bacilli on skin slit smear
  +
**'''Multibacillary (MB)''' disease has more than 5 skin lesions, with or without nerve involvement or bacilli on slit-skin smear (regardless of number of lesions)
  +
*Can also be classified based on general clinical appearance
  +
**'''Tuberculoid leprosy (TT)''' corresponds to paucibacillary
  +
**'''Borderline tuberculoid leprosy (BT)'''
  +
**'''Borderline leprosy (BB)'''
  +
**'''Borerdline lepromatous leprosy (BL)'''
  +
**'''Lepromatous leprosy (LL)''' corresponding to multibacillary disease
  +
  +
===Type I Reaction===
  +
  +
*A cell-mediated hypersensitivity reaction that can develop in the course of treatment
  +
*Also known as a '''reversal reaction''' due to the apparent worsening of the lesion
  +
*Occurs most commonly in the borderline cases and may signal progression to the cell-mediated tuberculoid end of the clinical spectrum
  +
  +
===Type 2 Reaction===
  +
  +
*A humorally-mediated hypersensitivity reaction that can develop in the course of treatment
  +
*Also known as '''erythema nodosum leprosum'''
  +
*Characterized by systemic illness and immune-complex deposition that appears as groups of tender subcutaneous nodules
  +
*May have other signs of vasculitis, including fevers, arthralgias, neuralgia, lymphadenopathy, orchitis, and dactylitis
  +
  +
===Physical Examination===
  +
====Commonly Affected Nerves====
 
{| class="wikitable"
  
{| class="wikitable"
βˆ’
! Trunk !! Palpation !! Sensation !! Movement !! Deformity
 +
!Trunk!!Palpation!!Sensation!!Movement!!Deformity
 
|-
  
|-
βˆ’
| Ulnar nerve
 +
|Ulnar nerve
βˆ’
| Just superior to medial epicondyle
 +
|Just superior to medial epicondyle
βˆ’
| Fifth digit and ulnar aspect of hand
 +
|Fifth digit and ulnar aspect of hand
βˆ’
| Fifth digit abduction
 +
|Fifth digit abduction
βˆ’
| Claw deformity of little and ring fingers
 +
|Claw deformity of little and ring fingers
 
|-
  
|-
βˆ’
| Median nerve
 +
|Median nerve
βˆ’
| Palmar wrist just medial to palmaris longus
 +
|Palmar wrist just medial to palmaris longus
βˆ’
| Lateral three fingers and palm
 +
|Lateral three fingers and palm
βˆ’
| Thumb abduction
 +
|Thumb abduction
βˆ’
| Claw deformity of first through third digits
 +
|Claw deformity of first through third digits
 
|}
  
|}
   
βˆ’
== Management ==
 +
== Differential Diagnosis ==
  +
βˆ’
=== WHO recommendations ===
  
  +
* '''Hypopigmented patches:''' [[vitiligo]], [[pityriasis alba]], [[post-inflammatory hypopigmentation]]
  +
* '''Erythematous macules and plaques:''' [[psoriasis]], [[tinea corporis]], [[nummular dermatitis]], [[syphilis]], [[mycosis fungoides]], [[sarcoidosis]]
  +
* '''Annular plaques:''' [[granuloma annulare]], [[tinea corporis]], [[psoriasis]]
  +
* '''Nodules:''' [[keloid]], [[dermatofibroma]], [[lymphoma]], [[metastasis]], [[sarcoidosis]], [[non-tuberculous mycobacteria]], [[fungal infection]]
  +
* '''Leonine facies:''' [[Paget disease of bone]], [[mycosis fungoides]], [[polyostatic fibrous dysplasia]], [[amyloidosis]], [[lichen myxedematosus]], [[leishmaniasis]], [[lipoid proteinosis]], [[progressive nodular histiocytosis]], [[mastocytosis]]
  +
* '''Reversal reaction:''' [[cellulitis]], [[drug eruption]], [[lymphoma]], [[tumid lupus]], [[Sweet syndrome]]
  +
* '''Erythema nodosum leprosum:''' [[erythema nodosum]], [[sepsis]], [[panniculitis]], flare of [[connective tissue disease]]
  +
* '''Neurologic findings:''' heritable neuropathies, polyneuropathy, entrapment neuropathy, cervicobrachial and scalenus syndromes, syringomyelia, [[amyloidosis]], [[neurofibroma]]
  +
** Leprosy never causes upper motor neuron lesions, and spares proximal muscles as well as deep tendon reflexes and proprioception
  +
** Sensory findings in leprosy are worse distally, though there may be islands of preserved sensation
  +
** Leprosy never involves CNS
  +
  +
== Diagnosis ==
  +
  +
* Worldwide, the diagnosis is made based on clinical findings with or without slit-skin smears or biopsy
  +
** At least one of: loss of sensation in a hypopigmented or reddish skin patch; thickened or enlarged peripheral nerve with loos of sensation and/or muscle weakness; or presence of acid-fast bacilli in slit-skin smear
  +
** A positive slit-skin smear is diagnostic of multibacillary disease
  +
* Slit-skin smear is made by scraping with a scalpel blade an opening of small slits made in pinched skin
  +
** The expressed tissue fluid is smeared on a slide and stained for acid-fast bacilli by Fite’s method
  +
** The pinching makes the skin relatively avascular, to minimize contamination with blood
  +
** Initial skin smears are usually taken from the routine sites of both earlobes, elbows, and knees, as well as several typical lesions from the patient
  +
* Skin biopsy may be more useful in high resource settings
  +
** Biopsy should be taken from the lesion edge of the most active margin of the most active lesion
  +
** Ideally full-thickness biopsy including dermis; can be a punch biopsy
  +
** Stained with Fite staining to maximize sensitivity
  +
  +
==Management==
  +
===WHO Recommendations===
 
{| class="wikitable"
  
{| class="wikitable"
βˆ’
! Disease !! Treatment
 +
!Disease!!Treatment
 
|-
  
|-
βˆ’
| Paucibacillary || 6 months of [[Is treated by::rifampin]], [[Is treated by::dapsone]], and [[Is treated by::clofazimine]]
 +
|Paucibacillary||6 months of [[Is treated by::rifampin]], [[Is treated by::dapsone]], and [[Is treated by::clofazimine]]
 
|-
  
|-
βˆ’
| Multibacillary || 12 months of [[Is treated by::rifampin]], [[Is treated by::dapsone]], and [[Is treated by::clofazimine]]
 +
|Multibacillary||12 months of [[Is treated by::rifampin]], [[Is treated by::dapsone]], and [[Is treated by::clofazimine]]
 
|-
  
|-
βˆ’
| Rifampin resistance || 6 months of at least two second-line drugs (below) with [[clofazimine]], followed by 18 months of one second-line drug with [[clofazimine]]
 +
|Rifampin resistance||6 months of at least two second-line drugs (below) with [[clofazimine]], followed by 18 months of one second-line drug with [[clofazimine]]
 
|-
  
|-
βˆ’
| Quinolone resistance || As for rifampin resistance, but without a fluoroquinolone
 +
|Quinolone resistance||As for rifampin resistance, but without a fluoroquinolone
 
|}
  
|}
   
βˆ’
=== National Hansens's Disease Program (US) ===
 +
===National Hansens's Disease Program (US)===
 
{| class="wikitable"
  
{| class="wikitable"
βˆ’
! Disease !! Treatment
 +
!Disease!!Treatment
 
|-
  
|-
βˆ’
| Tuberculoid (TT & BT) (i.e. paucibacillary)
 +
|Tuberculoid (TT & BT) (i.e. paucibacillary)
βˆ’
| 12 months of [[Is treated by::dapsone]] and [[Is treated by::rifampicin]]
 +
|12 months of [[Is treated by::dapsone]] and [[Is treated by::rifampicin]]
 
|-
  
|-
βˆ’
| Lepromatous (LL, BL, and BB) (i.e. multibacillary)
 +
|Lepromatous (LL, BL, and BB) (i.e. multibacillary)
βˆ’
| 24 months of [[Is treated by::dapsone]], [[Is treated by::rifampicin]], and [[Is treated by::clofazimine]]
 +
|24 months of [[Is treated by::dapsone]], [[Is treated by::rifampicin]], and [[Is treated by::clofazimine]]
 
|}
  
|}
   
βˆ’
=== Second-line antibiotics ===
 +
===Second-Line Antibiotics===
  +
βˆ’
* [[Is treated by::Clarithromycin]]
  
βˆ’
* [[Is treated by::Minocycline]]
 +
*[[Is treated by::Clarithromycin]]
  +
*[[Is treated by::Minocycline]]
βˆ’
* Fluoroquinolones: [[Is treated by::ofloxacin]], [[Is treated by::levofloxacin]], or [[Is treated by::moxifloxacin]]
  
  +
*Fluoroquinolones: [[Is treated by::ofloxacin]], [[Is treated by::levofloxacin]], or [[Is treated by::moxifloxacin]]
   
 
{{DISPLAYTITLE:''Mycobacterium leprae''}}
  
{{DISPLAYTITLE:''Mycobacterium leprae''}}
Line 105: Line 142:
 
[[Category:Mycobacteria]]
  
[[Category:Mycobacteria]]
   
βˆ’
=== Management of reactions ===
 +
===Management of Reactions===
 
{| class="wikitable"
  
{| class="wikitable"
βˆ’
! Reaction !! Management
 +
!Reaction!!Management
 
|-
  
|-
βˆ’
| Reversal reaction limited to skin
 +
|Reversal reaction limited to skin
βˆ’
| monitor clinically
 +
|monitor clinically
 
|-
  
|-
βˆ’
| Reversal reaction involving nerves
 +
|Reversal reaction involving nerves
βˆ’
| corticosteroids with slow taper, and [[rifampin]] changed to monthly from daily
 +
|corticosteroids with slow taper, and [[rifampin]] changed to monthly from daily
 
|-
  
|-
βˆ’
| Other reversal reaction
 +
|Other reversal reaction
βˆ’
| corticosteroids based on clinical judgment
 +
|corticosteroids based on clinical judgment
 
|-
  
|-
βˆ’
| Erythema nodosum leprosum with neuritis
 +
|Erythema nodosum leprosum with neuritis
βˆ’
| [[prednisone]] 1 mg/kg/day (40 to 60 mg/day), tapered over 2 to 4 weeks, possibly with [[thalidomide]] or [[clofazimine]] as a steroid-sparing agent
 +
|[[prednisone]] 1 mg/kg/day (40 to 60 mg/day), tapered over 2 to 4 weeks, possibly with [[thalidomide]] or [[clofazimine]] as a steroid-sparing agent
 
|-
  
|-
βˆ’
| Mild erythema nodosum leprosum
 +
|Mild erythema nodosum leprosum
βˆ’
| [[thalidomide]] 50 to 100 mg nightly
 +
|[[thalidomide]] 50 to 100 mg nightly
 
|}
  
|}
  +
  +
== Prevention ==
  +
  +
* Unclear whether household contacts require prophylaxis[[CiteRef::boodman2021le]]
  +
** Some experts recommend prophylaxis, particularly for exposure to multibacillary patients
  +
** Regimen unclear; most Canadian experts use single-dose [[rifampin]], in accordance with WHO recommendations
  +
** May instead do annual screening by physical examination for between 2 and 10 years

Latest revision as of 16:01, 5 November 2021

Background

Microbiology

  • Slow-growing Gram-positive and acid-fast bacillus

Epidemiology

  • About 1 million cases worldwide each year, but is rare in North America
    • Number may be underestimated due to difficulties with reliable diagnosis
  • Most commonly occurs in Southeast Asia (especially India) and Brazil
  • Decreasing incidence over the past several decades, likely due to short-course multidrug therapy starting in 1982
  • Humans are thought to be the main reservoir, but it has been found in animals as well (particularly nine-banded armadillos)
  • Transmitted most likely by respiratory droplets, though can also be transmitted by direct contact, transplacentally, through breast milk, and after animal exposure

Risk Factors

  • Age, with peaks in adolescence and β‰₯30 years
  • Adult men (compared to adult women)
  • Duration of contact with an infected patient, and the burden of bacilli in the patient

Pathophysiology

  • The clinical spectrum of disease depends on the host immune response to infection
  • A robust Th1 CD4 response causes tuberculoid leprosy, which is paucibacillary and well-controlled
    • Requires interferon-Ξ³
  • A Th2 CD4 response causes lepromatous leprosy, which is multibacillary and more progressive

Clinical Manifestations

  • Following exposure, about 95% clear it spontaneously
  • For those who do not, there is an incubation period of 3-5 years (with wide range) that is usually followed by indeterminate leprosy
    • Single, ill-defined, hypopigmented skin lesion
    • About 75% spontaneously resolve, with the other 25% progressing
  • Classic presentation is anaesthetic hypopigmented skin lesion with thickened nerves
  • Skin lesions can be: annular, asymmetric macules or plaques with central clearing and elevated borders (in tuberculoid) or symmetric, poorly-demarcated nodules and plaques or diffuse infiltration (lepromatous)
    • Lepromatous can also have xanthoma-likek or dermatofibroma-like lesions, leonine facies, and eyebrow alopecia

Spectrum of Disease

  • Clinical spectrum can be classified based on the number of lesions and burden of mycobacteria
    • Paucibacillary (PB) disease has 1 to 5 skin lesions, without bacilli on skin slit smear
    • Multibacillary (MB) disease has more than 5 skin lesions, with or without nerve involvement or bacilli on slit-skin smear (regardless of number of lesions)
  • Can also be classified based on general clinical appearance
    • Tuberculoid leprosy (TT) corresponds to paucibacillary
    • Borderline tuberculoid leprosy (BT)
    • Borderline leprosy (BB)
    • Borerdline lepromatous leprosy (BL)
    • Lepromatous leprosy (LL) corresponding to multibacillary disease

Type I Reaction

  • A cell-mediated hypersensitivity reaction that can develop in the course of treatment
  • Also known as a reversal reaction due to the apparent worsening of the lesion
  • Occurs most commonly in the borderline cases and may signal progression to the cell-mediated tuberculoid end of the clinical spectrum

Type 2 Reaction

  • A humorally-mediated hypersensitivity reaction that can develop in the course of treatment
  • Also known as erythema nodosum leprosum
  • Characterized by systemic illness and immune-complex deposition that appears as groups of tender subcutaneous nodules
  • May have other signs of vasculitis, including fevers, arthralgias, neuralgia, lymphadenopathy, orchitis, and dactylitis

Physical Examination

Commonly Affected Nerves

Trunk Palpation Sensation Movement Deformity
Ulnar nerve Just superior to medial epicondyle Fifth digit and ulnar aspect of hand Fifth digit abduction Claw deformity of little and ring fingers
Median nerve Palmar wrist just medial to palmaris longus Lateral three fingers and palm Thumb abduction Claw deformity of first through third digits

Differential Diagnosis

Diagnosis

  • Worldwide, the diagnosis is made based on clinical findings with or without slit-skin smears or biopsy
    • At least one of: loss of sensation in a hypopigmented or reddish skin patch; thickened or enlarged peripheral nerve with loos of sensation and/or muscle weakness; or presence of acid-fast bacilli in slit-skin smear
    • A positive slit-skin smear is diagnostic of multibacillary disease
  • Slit-skin smear is made by scraping with a scalpel blade an opening of small slits made in pinched skin
    • The expressed tissue fluid is smeared on a slide and stained for acid-fast bacilli by Fite’s method
    • The pinching makes the skin relatively avascular, to minimize contamination with blood
    • Initial skin smears are usually taken from the routine sites of both earlobes, elbows, and knees, as well as several typical lesions from the patient
  • Skin biopsy may be more useful in high resource settings
    • Biopsy should be taken from the lesion edge of the most active margin of the most active lesion
    • Ideally full-thickness biopsy including dermis; can be a punch biopsy
    • Stained with Fite staining to maximize sensitivity

Management

WHO Recommendations

Disease Treatment
Paucibacillary 6 months of rifampin, dapsone, and clofazimine
Multibacillary 12 months of rifampin, dapsone, and clofazimine
Rifampin resistance 6 months of at least two second-line drugs (below) with clofazimine, followed by 18 months of one second-line drug with clofazimine
Quinolone resistance As for rifampin resistance, but without a fluoroquinolone

National Hansens's Disease Program (US)

Disease Treatment
Tuberculoid (TT & BT) (i.e. paucibacillary) 12 months of dapsone and rifampicin
Lepromatous (LL, BL, and BB) (i.e. multibacillary) 24 months of dapsone, rifampicin, and clofazimine

Second-Line Antibiotics

Management of Reactions

Reaction Management
Reversal reaction limited to skin monitor clinically
Reversal reaction involving nerves corticosteroids with slow taper, and rifampin changed to monthly from daily
Other reversal reaction corticosteroids based on clinical judgment
Erythema nodosum leprosum with neuritis prednisone 1 mg/kg/day (40 to 60 mg/day), tapered over 2 to 4 weeks, possibly with thalidomide or clofazimine as a steroid-sparing agent
Mild erythema nodosum leprosum thalidomide 50 to 100 mg nightly

Prevention

  • Unclear whether household contacts require prophylaxis1
    • Some experts recommend prophylaxis, particularly for exposure to multibacillary patients
    • Regimen unclear; most Canadian experts use single-dose rifampin, in accordance with WHO recommendations
    • May instead do annual screening by physical examination for between 2 and 10 years

References

  1. ^ boodman2021le 

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