Introduction: (NTMs). Classification The most commonly followed

Introduction:

 

The genus Mycobacterium, belonging to the phylum Actinobacteria, family
Mycobacteriaceae consists of over 190 pathogenic and non-pathogenic species. Mycobacterium tuberculosis and M. leprae have been the most studied
bacteria in the genus, owing to the higher prevalence of the diseases caused by
them. The other members of the genus are under-investigated and have gained more
attention recently due to an increase in the reports of opportunistic infections
by these species.

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Non tuberculosis mycobacteria (NTM) are aerobic,
non-motile, acid fast staining bacilli found ubiquitously in the environment.
These organisms include over 160 species and are addressed by several names,
atypical mycobacteria, Mycobacteria
other than tuberculosis (MOTT), Non tuberculosis mycobacteria (NTMs).

 

 

Classification

 

The
most commonly followed classification of this group is based on their rate of
growth and pigment production (Runyon, 1959). They are grossly divided into two
groups comprising four subtypes: 1. Slow growers (Type I-III) and 2. Rapid
growers (Type IV). Type I (photochromogens), Type II (scotochromogens) and Type
III (non-photo-chromomgens). Group 1 contains organisms that take more than 7
days to growGS1 , which are classified Type I
if producing yellow-range pigment in the presence of light , Type II if producing
orange pigment in the dark and red pigmentation in light and TypeGS2  III if producing weak or no
pigments. Rapid growers, take less than 48 hrs to grow and are grouped under
Type IV.

 

Type I

M. kansasii

M.
marinumGS3 

 

Type II

M. gordonae

M. scrofulaceum

 

Type III

MAC – M. avium, M. intracellulare

M. xenopi

M. ulcerans

M. terrae

M. haemophilum

 

 

Type IV

M. fortuitum

M. abscessus

M. chelonae

 

S- R morphotypesGS4 

 

Based on the morphology of the colonies
on solid media, Mycobacteria are
classified into S –smooth or R- rough morphotype. There is a remarkable
difference in the virulence and the host response against the two morphotypes
of the same clones!!

 

GS5 R morphotype of M. abcessus were
shown to stimulates the innate response in macrophages through the TLR2 whereas
the S morphotype does not. The GPL present on the surface of the S type has
been implicated in the stimulation of TLR2. He also suggested that the GPL on S-forms
masks the cell wall lipids that are involved in the stimulation and the R
revertants that have the lipids unmasked are capable of causing inflammation of
the respiratory tract. Spontaneous reversion between the S and R morphotypes of
the same colonies are involved in the capability of the species to switch
between colonization by biofilm formation and virulence. The glycopeptidolipids
(GPL) on the cell wall of the S morphotype has been implicated in this
difference in characteristics (Howard & Rhoades, 2006). A clinical study
reported a patient suffering from CF with M.abccessus S morphotype lung
infection progressing to acute lung failure due to the reversion to R
morphotype, indicating the importance of the morphology in virulence
(Catherinot, 2008).

 

 

MycobacterialGS6 
cell structure

 

Cell WallGS7 

The mycobacterial cell wall is a thick,
dense, hydrophobic structure involved in cell growth, antibiotic resistance and
virulence. It is made up of long chain fatty acids called mycolic acid and a heteropolysaccharide,
arabinogalactan, linked by phosphodiester bonds. The arabinogalactan acts as a
bridge between the mycolic acid and the inner peptidoglycan layer. The complex
is commonly termed as mycolyl-arabinogalactan-peptidoglycan (mAGP). This
asymmetrical lipid bilayer model was proposed in the 80’s by Minikin and is
currently the widely accepted model of mycobacterial cell wallGS8 .

 

Peptidoglycan

The inner layer of the cell wall
complex, covering the plasma membrane in mycobacterium is made up of
peptidoglycan, a rigid structure and highly crosslinked structure composed of
repeating disaccharides, N-acetylglucosamine and modified muramic acid linked
by peptide bonds. (Lederer,1975). The peptidoglycan of mycobacterium is
classified under A1?, unmodified peptidoglycan, according to the Schiefer and
Kandler classification. The muramic acid group is present in both the
N-glycolyl (NGlyc) and N-acetyl (NAc) form as opposed to the NAc form seen in
E.coli (Mahapatra, 2005).
The biosynthesis of this layer takes place in an “inside to outside” manner.

 

Arabinogalactan

Arabinogalactan is a heteropolymer layer,
predominantly made of arabinose and galactose (Amar and Vikas). They
are found in the furanoid ring form as D-arabinofuranose and D-galactofuranose
which are very rare in nature (McNeil,1987). The
arabinogalactan layer is linked to the internal PG layer by the linker unit
made up of rhamonose residues linked to the galactose residue forming D- Galf (1 ? 4)-l-Rhap-(1 ? 3)-d-GlcNAc
(McNeil, 1990).

 

Mycolic acid

 

The characteristic feature of the
mycobacterial cell wall is the precence of an outer layer of mycolic acids,
which are very long chain ?-alkyl ?-hydroxy fatty acids (Gebhardt, 2007). This hydrophobic
layer plays a major role in the virulence and tolerance to dehydration and
chemical damage of M. tuberculosis (Forrellad,2013,
Kremer,2002). The
mycolic acid layer is esterified to the inner arabinogalactan layer and to
glycerol and trehalose. The esterification to trehalose produces trehalose
mono/dimycolates, which are releases free Mas involved in biofilm formation (Ojha, 2010GS9 ).

 

 

The
hydrophobicity of the cell wall provides a low permeability, leading to
increased resistance against chemical treatments.

 

 

NTM are environmental bacteria, found
extensively in water bodies and also in the air, soil, domestic and wild animalsGS10 .
Moreover, NTM form biofilms, which makes them resistant to water treatment and
disinfection, e.g. bychlorination, allowing them to persist in man-made water
supplies. Human infections by NTM are rare compared to MTB; however NTM have
been shown to cause clinical symptoms which vary widely based on the organism
and the risk factorsGS11 .
Moreover, asymptomatic persistence of the bacteria is seen in a high fraction
of populationGS12 
(Griffith,
2007).

 

Mycobacteria
have been shown to be rapidly phagocytosed by protozoa, owing to the high
hydrophobicity of the bacterial cell wall. Depending on the species of
bacteria, the A castellani either survived without injury (M.avium,  M.ulcerans) or destroyed within 5 days (
M.smegmatis, M.fortuitum). Studies show that M avium can interact with A.
castellanii, , Tetrahymena pyriformis, Dictyoselium discoideum and interact
saprozoically with Acanthameoba polyphaga (Steinert, 1998). There
is a strong co relation between the virulence of the species to animal cells
and their capability to survive within protozoa. Highly pathogenic M.avium
prevents phagolysosome fusion and survive in A.castellanii whereas M.smegmatis,
a non pathogenic sepcies is not capable of the same. Bacteria grown in amoeba
also show enhanced entry and survival in mammalian cells. (Cirillo, 1997).

 

 

Epidemiology

 

NTMs are distributed worldwide, yet they
show strong geographic diversity, owing to the fact that they are environmental
bacteria. Mycobacterium avium,
intracellularae and chimera,
grouped under MAC, mycobacterium avium
complex, are the most common cause of NTM infections in humans (ATSGS13 ).
M. gordonae and M xenopi and among the second and third most frequently isolated
NTMs, predominantly in the west (Hoefsloot, 2013). Among
RGM, M abscessus and M fortuitum are the most commonly
isolated species, with a recent increase in the number of M abscessus cases in CF patients, accounting for over half of all
NTMs isolated (Kathryn,
2014).

 

There are several reports that suggest
that there is a steady increase in NTM infections worldwide, in recent years. In
the UK the incidence rates increased from 5.6/100,000 to 7.6/100,00 between
2007- 2012
(Shah. 2016). Estimates from the USA suggest an
increase in pulmonary NTM infections across all regions (Adjemian, 2012) and ranges from 1.4 to 6.6/100000 (Kendall ,2013). IN Eastern countries like Japan, the
incidence of pulmonary NTMs has been estimated at 14.7/100000 in 2014 (Namkoong, 2014).

 

 

Mode of
transmission

 

The mode of transmission of NTMs leading
to an infection is not clearly defined. The hydrophobicity of the mycobacterial
cell wall leads to aerosolization of the bacteria from contaminated water bodies
(Parker, 1983). Aerosols
are considered the most primary mode of transmission in NTMs (Halstrom,
2015).

 

Person to person spread of NTMs are
considered highly unlikely, however, recent evidences from case reports show
possible spread of M abscessus and M a massiliense among patients with CF (Bryant, 2013). Whole
genome sequencing of multi drug resistant M
abscessus from clinical isolates around the world has also indicated
transmission of via fomites and aerosols (Bryant, 2016)

 

Nosocomial transmission of NTM infection
have been described in which the hospital water supply plays a major role.
Contaminated devices like injections, bronchoscopes and dialysis solutions have
also been shown to cause infection in patients (Phillips,2001).

 

 

GS14 

Risk Factors:

 

NTM infections is predominant as an
opportunistic infections with majority of the cases being linked to immunocompromised
individualsGS15 .

 

Individuals with underlying lung
disorders like Chronic
Obstructive Pulmonary Disease (COPDGS16 ),
pneumoconiosis, and asthma are at a higher risk of pulmonary infections due to
NTMs (Official
ATS). Cystic
Fibrosis (CF)GS17 
is the most commonly observed risk factor for pulmonary NTM colonization and
infection, specifically with M avium
and M abscessus (Hill, 2012). There
are several reports that suggest co infection of NTMs and MtB (Ishiekwene, 2017,
Aliyu,
2013, Hoza,
2016) often leading to misdiagnosis.

 

Individuals who are immunosuppressed are
at a higher risk of disseminated infection with NTMs. (Winthrop,
2015). A substantial number of disseminated NTM infections are reported in
patients suffering from AIDS, especially in cases with very low CD4 cell counts
(Karkousis,
2004). The introduction of Highly Active Antiretroviral Therapy (HAART) has
reduced the odds of NTM infection in AIDS patients but remains a common opportunistic
infection in HIV infected patients (Kobayashi,
2016)

 

Genetic abnormalities in CFTR and AAT
(?-I-antitrypsin) and defects in immune mediators such as the IL-12, IFN –?
secretion are also considered as pre-disposing factors. (Chan 2013, Official
ATS). Patients with rheumatoid arthritis and other connective tissue
conditions undergoing TNF? inhibitor therapy, individuals with lower BMI, old
age and severe Vitamin D deficiency also fall under high risk category (MA
Lake, 2016).

 

 

Clinical
Presentation:

 

The clinical manifestation of NTM
infections can be distinctly divided into i. Skin and Soft tissue, ii. Lymphadenitis,
iii. Pulmonary, iv. Disseminated disease. The species associated with as well
as the treatment regimens vary based on the type of infection.

 

Skin & Soft Tissues

Skin and soft tissue
infection (SSTIs) caused by NTM, particularly on the hands, elbow, knee and
foot, are highly underdiagnoGS18 sed.
Cosmetic procedures, surgery and immunosuppression are considered the major
risk factors (Atkins,
2014). Rapidly growing species like M.fortuitum, M.cholonae, M.abcessus, M.ulcerans and M.marinum are the most
common cause of SSTIs (Kothavade.
RJ, 2013).

 

 

 

Lymphadenitis

Infection of the lymph node
by atypical mycobacteria is common in children owing to the fact that the
spread is primarily through the oral route. Hands and other objects coming in
contact with the oral mucosa provides an opportunity for the bacteria to enter
the body. In most cases there is a unilateral infection of the cervical lymph
node that does not resolve by antibiotic treatments (Hazra,1999).
Surgical removal of the swollen lymph node is the best solution. M.scrofulaceum
was previously the most common cause of the condition, however many other
species have been increasingly implicated, M.avium being the most common (Wolinsky, 1995).

 

 

Pulmonary Infection

In non-AIDS patients, older
people with pre-existing lung disorder or structural defects, the disease is
indistinguishable from tuberculosis. The symptoms include cough, excess sputum,
fatigue, fever, weight loss, upper lobe fibrosis, cavitation and pleural
thickening (Piersimoni,
2008). The disease progression is very slow.

 

In AIDS patients however the
infection is rapid and causes mediastinal or hilar adenopathy (Trotoli,
2009). The major cause of the infection is the immunocompromised state of
the patients. The recent increase in the use of highly active anti-retroviral
therapy (HAART) for treatment has reduced the incidence.

 

Disseminated disease

Disseminated disease is the
most common type of NTM infection seen in immunocompromised individuals as in
the case of AIDS. It frequently occurs when the CD4 cell count drops below
50/µl (Horsburgh, 1996).The
route of entry in this case is either respiratory or the oral mucosa. Symptoms
include abdominal pain, weight loss, fever, diarrhea, sweating, splenomegaly
and hepatomegaly (Nightingale
SD, 1992). There are studies that show that disseminated disease causes
high mortality in AIDS patients even with the ART treatments (Kobayashi,
2016).

 GS1On plate?

 GS2Be consistent with capitalization

 GS3I think this
would best in a figure. You should set this biochemical classification in
context to the phylogeny/ grouping according to WGS, 16SRNA.,e.g. Tortoli,
2017. Maybe add one or two sentence how the distinction from MTB and others is.

 GS4Should go up in the classification section. Probably between
biochemical and genetics classification

 GS5Just reference

 GS6I think you need a subheading here

 GS7References for this section

 GS8This text will be much better with a figure illustrating what you
describe.

 GS9

 GS10A or two sentence about the interaction with protozoa?

 GS11References in this section

 GS12Reference

 GS13Check numbers in the Thorax Society data (I put this in your lit
folder). Include statement about M. abcessus cases.

 GS14Consider moving in pathogenesis section.

 GS15 Expand on different health factor from here on

 GS16Define all abbreviations

 GS17Highlight abcessus

 GS18references