Microbes in Health and Diseases

**37**

**Chapter 3**

**Abstract**

Human Health

microbiome impact on human health.

**1. General introduction**

hazard, pathogens, raw hide and skin and tanned leather

The Role of Leather Microbes in

*Richard O. Oruko, John O. Odiyo and Joshua N. Edokpayi*

Leather tanned from raw hides and skins have been used to cover and protect

**Keywords:** human health, human microbiome, leather-making processes, microbial

Skin is the largest organ in the animal's body and acts as the entry point of microbes from the outside world [1, 2]. The diverse population of microbes found in human and animal resides on the skin. About 1000 different species of bacteria, fungi, viruses and other microbes live on the skin. The majority are harmless and even beneficial to human and animal hosts. Microbe colonisation of the skin is normally variable and relies on endogenous host factors, topographical location and exogenous environmental factors [3]. Over a long period of time, microbes, humans and other animals have established complex relationships with each other [2]. For example, to remain healthy, humans and other animals require microbes and many microbes also require specific environments provided by the human and the animal's bodies to sustain their lives. Humans, other animals, and microbes depend on these interactions to grow and stay healthy. Diverse species of microbes reside in different places in and on human and other animals and they are adapted to those conditions and places. Human, animals and their microbial flora form a complex ecosystem whose equilibrium acts as a reliable adaptation system [2]. In realisation

the human body since early man. The skin of an animal carries thousands of microbes. Some are beneficial and protect the animal while others are pathogenic and cause diseases. Some microbes have no defined roles in animals. These microbes end up in the human body through contact with the animal skin. In recent years, the human body has been studied as an ecosystem where trillions of microorganisms live as a community called microbiome. Humans need beneficial microbes like *Bacillus subtilis* on the skin surface to stay healthy. Many microbes need the human body to survive. Not many studies have looked into the close link between animal leather and the human microbiome. The assumption is that conventional leather processes inhibit the pathogens on skins from carrying any risk of microbial hazard to the human body. This chapter identifies endemic microbes of "animal skin microbiome" that withstand extreme acidity and alkalinity of leather manufacture and their transmission to humans. Some cause allergic reactions, skin lesion, infections or death to tannery employees with weakened immune systems. This promotes the need to look at leather product

#### **Chapter 3**

## The Role of Leather Microbes in Human Health

*Richard O. Oruko, John O. Odiyo and Joshua N. Edokpayi* 

#### **Abstract**

 Leather tanned from raw hides and skins have been used to cover and protect the human body since early man. The skin of an animal carries thousands of microbes. Some are beneficial and protect the animal while others are pathogenic and cause diseases. Some microbes have no defined roles in animals. These microbes end up in the human body through contact with the animal skin. In recent years, the human body has been studied as an ecosystem where trillions of microorganisms live as a community called microbiome. Humans need beneficial microbes like *Bacillus subtilis* on the skin surface to stay healthy. Many microbes need the human body to survive. Not many studies have looked into the close link between animal leather and the human microbiome. The assumption is that conventional leather processes inhibit the pathogens on skins from carrying any risk of microbial hazard to the human body. This chapter identifies endemic microbes of "animal skin microbiome" that withstand extreme acidity and alkalinity of leather manufacture and their transmission to humans. Some cause allergic reactions, skin lesion, infections or death to tannery employees with weakened immune systems. This promotes the need to look at leather product microbiome impact on human health.

**Keywords:** human health, human microbiome, leather-making processes, microbial hazard, pathogens, raw hide and skin and tanned leather

#### **1. General introduction**

Skin is the largest organ in the animal's body and acts as the entry point of microbes from the outside world [1, 2]. The diverse population of microbes found in human and animal resides on the skin. About 1000 different species of bacteria, fungi, viruses and other microbes live on the skin. The majority are harmless and even beneficial to human and animal hosts. Microbe colonisation of the skin is normally variable and relies on endogenous host factors, topographical location and exogenous environmental factors [3]. Over a long period of time, microbes, humans and other animals have established complex relationships with each other [2]. For example, to remain healthy, humans and other animals require microbes and many microbes also require specific environments provided by the human and the animal's bodies to sustain their lives. Humans, other animals, and microbes depend on these interactions to grow and stay healthy. Diverse species of microbes reside in different places in and on human and other animals and they are adapted to those conditions and places. Human, animals and their microbial flora form a complex ecosystem whose equilibrium acts as a reliable adaptation system [2]. In realisation

of this important complex relationship, the United States government in 2008 launched the human microbiome project. The above-mentioned project emphasised the need for comprehensive characterisation of different body parts for microbial communities of humans [4].

Microbiome research study in animals has lagged behind human research because of lack of investment, towards relating the animal microbiome in human health and disease [4]. "Animal microbiome" is wider in scope than humans, and as such, there is a lot of data specific to each animal species, their body parts, and their products. However, there is a need for animal products microbiome data as that of the human condition, particularly in One Health mindset concept. In this concept, it is necessary to consider the health of the animal and their products, as being closely linked to the health of humans. Globally everybody uses animal skin and leather products in one way or the other in their daily lives. This implies that microbes in them might be interacting with human health either positively or negatively. Microbiome research in this topic is still in nascent's stage and needs to be studied in detail to show the link as this is important, due to the fundamental biology of these invisible microbes in animal skins/leather products and their roles in human health.

#### **2. Microbes reported in animal skins and leather products**

 Live animals bodies host thousands and thousands of microbes. Some are harmful while others are not. Among the pathogenic microbes are those which can cause diseases in animal and human. These diseases are known as zoonotic diseases. A zoonotic disease or zoonosis is defined as any disease of animals that can be transmitted to people [5]. The first recognised zoonoses with an occupational relationship relevant to the leather industry are those that cause skin lesions and have short incubation periods, such as ringworm infections, cutaneous anthrax and glanders [5]. Anthrax infection among tannery workers has been reported in Bangladesh [6]. The first documented case of anthrax in the United States of America occurred in Florida state in 1974. Cutaneous anthrax occurred due to contact with a goat skin bongo drum bought in Haiti while inhalation anthrax occurred in Scotland in 2006. This happened because of handling contaminated hide drums from West Africa [7]. The most common fungal disease in animal skin is ringworm, also known as *Dermatophytosis*. This is not a worm at all, but a fungus called *Dermatophytes* that grows on the skin. It affects workers who handle raw skins without wearing protective gears in the tanning industry [7].

 Other microbes on the live animal skin only cause infection and damage to the skin [8]. It is yet to be known if they can affect humans that handle them. The most important bacterium that causes damage to the skin during the animal's life is *Dermatophilus congolensis*, which occurs as a secondary infection, in bovine demodicosis lesions. *Staphylococcus aureus, Staphylococcus albus*, and *Streptococcus pyogenes* are all reported to be associated with lesions of demodectic mange in sheepskin. *Staphylococcus aureus, Corynebacterium pyogenes, Pseudomonas aeruginosa, Bacillus subtilis*, and *Morexella bovis* have been isolated as secondary infections where bovine demodicosis was found to be present [8]. Some of these microbes have potential to cause pathogens on the host. They are normally transferred from the animal skin to human skin whenever people get into contact with the live animal in the fields or dead animal skin during slaughter. This is common in developing countries where not all skins that reach curing premises and tanneries come from licenced slaughterhouses. Some originate from individual homes; such skins are called "fallen hide/skin". Some

#### *The Role of Leather Microbes in Human Health DOI: http://dx.doi.org/10.5772/intechopen.81125*

 come from individual homes located deep in the interior villages, where veterinary services are lacking. This results into skins of a diseased animal, which have not been inspected by a veterinary inspector. The potential to infect the people handling them is always very high if they are affected by the zoonotic disease. This is the first stage of exposure to the workers in the leather manufacture chains and therefore it has become a source of concern about tannery worker health.

 As soon as the animal is slaughtered the processes of decay on the flesh side begins. Animal skin undergoes microbiological decay since as an organic material it is a source of food for microbes [8]. Organisms involved in hide and skin putrefaction in slaughterhouses include *Staphylococci* and *Micrococcus* organisms. The majority of *Staphylococci* isolated so far includes *Staphylococcus xylosus, Staphylococcus sciuri, Staphylococcus cohnii, Staphylococcus simulans, Staphylococcus hyicus* and *Staphylococcus epidermidis*. The *Micrococcus* found in this study was *Micrococcus varians* [9]. In one study, 414 micro-organisms from 80 cattle hide and 80 sheep skin swab samples were isolated in Sudan. Out of the above figure, 134 isolates were characterised from fresh and washed cattle hides and sheep skins which included;- *Staphylococcus spp., Micrococcus spp., Corynebacterium spp., Aerococcus homorri, Enterococcus casseliflavus, Aerococcus viridans, Enterococcus faecalis, Gemella haemolysans, Stomatococcus spp., Pseudomonas spp*. and *Escherichia coli*. The samples taken from the slaughterhouse hides and skins were predominately *Staphylococcus spp., Micrococcus spp., Bacillus spp*. and *Corynebacterium spp*. along with *Staphylococcus albus*, *Streptococcus pyogenes, Pseudomonas aeruginosa, Bacillus subtilis* and *Corynebacterium pyogenes* [10].

 From the slaughterhouses, the skins are normally moved to curing premises for preservation before they are delivered to the tannery for processing into leather. Preservation methods used range from sun drying, air drying on frames, salting, brining and chilling. Although these methods stop putrefaction of hides and skins, some microbes still survive and eventually move to the tanning process. Bacteria isolated from hides and skins delivered directly to the tannery without prior treatment include *Staphylococcus spp., Micrococcus spp., Corynebacterium spp., Lactobacillus jensenii, Streptococcus spp., Enterococcus spp., Stomatococcus mucilaginous, Bacillus spp., Aerococcus viridans, Pseudomonas vulgaris biogroup II, Escherichia coli* and *Pseudomonas spp.* 

Hides and skins showing signs of putrefaction in the curing premises normally give off an offensive odour and show hair slipping on the grain side. Bacteria involved in putrefaction of those areas have been identified as *Staphylococcus saccharolyticus, Staphylococcus capitis, Staphylococcus hyicus, Micrococcus lylae, Corynebacterium bovis, Cory xerosis, Lactobacillus jensenii, Bacillus cereus, Staphylococcus intermedius, Bacillus amylogliguesta, Staphylococcus saprophyticus, Staphylococcus auricularis, Staphylococcus hominis, Staphylococcus epidermidis, Staphylococcus xylosus, Micrococcus varians and Micrococcus lentus*. In general *Staphylococcus spp., Micrococcus spp., Corynebacterium spp., Bacillus spp., E. coli* and *Pseudomonas spp* were found to be common [10]. The following bacteria; *Staphylococcus gallinarum, Dermacoccus nishinomiyaensis, Gardnerella vaginalis* and *Staphylococcus equorum* were isolated from putrefied hides and skins for the first time [10]. *Staphylococcus chromogenes, Staphylococcus xylosus, Staphylococcus kloosii*  and *Bacillus mycoides* were found to be growing well in dried hides and skins [11]. The *Staphylococcus spp*. and *Micrococcus spp*. are therefore considered to be part of the normal microflora of cattle hides and sheep skins [11, 12].

Gram-positive and Gram-negative bacteria have also been isolated from goat and sheepskins. Gram-positive bacteria were identified to be 78.7% [13]. The isolated bacteria were identified as *Bacillus cereus, Bacillus subtilis, Bacillus megaterium, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus fermentum, Micrococcus* 

 *luteus, Neisseria flavescens, Neisseria sicca, Proteus mirabilis, Proteus spp, Pseudomonas spp, Staphylococcus luteus, Staphylococcus aureus, Staphylococcus epidermis,* and *Streptococcus faecalis*. The writers found out that the Gram-positive Bacilli and Cocci with proteolytic activity are the most responsible for the degradation of goat and sheep skins [13]. These microbes might end up on the bodies of workers in the leather manufacture chain. Their consequences on the health of these tannery workers could be detrimental if they are potentially pathogenic.

 Many curing premises use salt to preserve green hides and skins. In the salted cattle hides and sheepskins the following bacteria have been isolated; *Staphylococcus spp, Micrococcus spp., Corynebacterium spp., Enterococcus spp., Stomatococcus mucilaginosus, Bacillus spp., Moraxella bovis, Proteus vulgaris biogroup II, Pseudomonas spp.* and *Escherichia coli* [14]. These bacteria are considered salt-resistant species especially *Staphylococcus, Micrococcus, Corynebacterium, Stomatococcus, Lactobacillus*, and *Bacillus*. The writers consider them halophilic bacteria since they can grow well in salt concentrations of 5–15% [15]. Other reported studies indicate that on a salted raw hide, the proliferation of halophilic bacteria results in the production of a range of pigments giving red and violet spots. From these coloured spots *Micrococcus roseus, Micrococcus luteus* and *Micrococcus morrhuae* have most frequently been isolated [15, 16]. Fungi have also been confirmed to be natural inhabitants of hides/skins. Fungi species can tolerate high NaCI concentrations of 20–30% (w/v) [17]. This is a higher concentration than that tolerated by bacteria. *Aspergillus terreus, Aspergillus niger, Aspergillus fumigatus, Penicillium restrictum, Penicillium citrinum, Altemia spp*. and *Cladosporium spp.* were isolated from salted sheepskins [17]. From the curing premises, the raw hides and skins are taken to tanneries for processing. The first stage of tanning is the beamhouse yard.

 In the beamhouse operations, six perforation-causing strains of bacteria have been isolated and identified as belonging to *Bacillus subtilis, Bacillus megaterium, Bacillus anthracoides, Bacillus pumilus* and *Pseudomonas aeruginosa*. They were isolated from soaking water for raw skin in the beam house [18]. An environmental mycological survey carried out at the liming section of the Tannery and Footwear Corporation (TAFCO) at Kanpur, India, in 1985, isolated and characterised 33 fungal species. *Aspergillus spp*. and *Penicillium spp*. were the two predominantly isolated fungal species. The other isolated species were *Alternaria spp., Cephalosporium spp., Chaetomium spp., Cladosporium spp., Cunninghamella spp., CUNularia spp., Drechslera spp., Fusarium spp., Mucor spp., Phoma spp., Rhizopus spp.* and *Trichoderma spp* [18]. The following isolated fungal species from beamhouse have been reported to have potential allergens. They include *Aspergillus flavus, Aspergillus oryzae, Aspergillus sulphureus, Aspergillus sydowii, Aspergillus terreus, Mucor geophila and Rhizopus stolonifer* [18]*.* Various fungal species such as *Penicillium spp., Aspergillus spp., Alternaria spp., Scopulariopsis spp.* and *Cladosporium spp.* have also been isolated from 14 tanneries in Istanbul, Turkey. *Penicillium spp*. was found to be the most commonly isolated fungal species followed by *Aspergillus spp* [19]. The authors, therefore concluded that the allergen from the isolated fungal species may be the reason for the development of respiratory infections in tannery workers thus the need to pay more attention to the skin microbes from leather industries even those which are undergoing processing.

From the beamhouse yard, the leather processing moves to tanyard operation. Here we have chrome-tanned leather (known technically as wet blue) with the formation of red spots which is a frequent phenomenon in the tanned leather. The originators of the red colour on tanned leather have been identified as *Paecilomyces ehrlichii* (=*Penicillium klebanii*), *Penicillium aculeatum, Penicillium purpurogenum*  and *Penicillium Roseopurpureum* [20]. The red spots on the wet blue are not limited to one type of leather only, since these fungi attack and cause red colouration

#### *The Role of Leather Microbes in Human Health DOI: http://dx.doi.org/10.5772/intechopen.81125*

even in box sides, horse chevreau, pig-skin splits and goat skins, among others. From tanyard operations, leather processing moves to crust and finishing yard. During drying of finished leathers, moulds may also develop due to favourable humidities and temperatures inside the drying rooms [20]. On the other hand, the biodeterioration becomes visible as spots of various sizes in green, yellow-brown, dark-brown, grey and brown-green shades on the finished leather. Associated with this type of damage, various workers have isolated *Aspergillus ochraceus, Aspergillus wentii, Penicillium rugulosum, Penicillium funiculosum, Penicillium variotii* and *V. glaucum*. They are noted for attacking skin substrates with high grease content, but a far larger range of fungal types than these cause damage during leather drying process.

 Major damage on finished leathers is caused by fungi. The types of fungus that are encountered in tanneries are well-known contaminants of leather materials [21]. Those that are frequently isolated includes; *Penicillium chrysogenum, Penicillium luteum, Penicillium brevicompactum, Penicillium decumbens, Penicillium rugulosum, Penicillium aculeatum, Penicillium funiculosum, Aspergillus niger, Aspergillus fumigatus, Aspergillus ochraceus, Aspergillus wentii, Aspergillus < avus-oryzae (group), Mucor mucedo, Rhizopus nigricans, Paecilomyces variotii, S. brevicaulis, V. glaucum* and *Trichoderma viride.* The above mentioned fungi utilise tanning conditions for their growth and development, hence they can even be found on the finished leathers as well as on the surface of vegetable-tanning solutions. In these solutions, they cause fermentation of the tanning agent due to the effect of "tannase" enzymes especially in the production of vegetable-tanned sole leathers. A poor growth of the yeasts *Candida albicans* and the moderate growth of *Staphylococcus aureus* were observed on the finished leather specimen [21]. The reported researches have proved that *Penicillium, Aspergillus*, and *Trichoderma* are the main microbes growing on the wet blue leather [22].

A new kind of bacterial defect, different from well-known bacteria-borne defects (like hair slip, red discolouration, and grain pilling) on the leather has also been identified. It is called the bio-film. A biofilm defect is explained to be composed of a single or multiple species of bacteria, embedded in the polyanionic extracellular polymeric substances which are attached to the surface of leather [23]. Different bacterial and fungal species, for example, the Genus of *Bacillus, Corynebacterium, Clostridium, Staphylococcus, Penicillium, Aspergillus, Paecilomyces, Candida*, and *Cryptococcus* are responsible for destruction and degradation of leather and their products [24, 25]; therefore, these microbes with potential pathogens could pose a real threat to the health of tannery workers and even the population that use leather goods.

 Finished leather is normally used to make leather items like the belt, purse, shoes, upholstery and boots, among others. A study carried out around 2015 in Mauritius found that purses used by almost everybody globally could be a potential reservoir for bacteria, in particular, those made out of leather and synthetic materials [26]. In roughly half of the purses sampled in that study, there was only a single type of bacterial growth isolated and identified. In the other half of the samples, there was the identification of mixed growth. In most cases, these microbes are normally carried harmlessly on the skin of most people. It is reported by some authors that infection only occur if a person has a weak immune system or if the skin is wounded, allowing the bacteria to enter the body [26]. Therefore, it is worth noting that even finished leather items are potential sources of pathogenic microbes. Besides that, finished leather products such as footwear may be colonised by fungi and bacteria [27]. The carbon source for bacterial growth is sweat compounds of footwear users and other compounds contained in shoe materials. Footwear, especially those often and intensively used, provides an ideal

 environment for microbial growth, including pathogenic species, causing athlete's foot (tinea pedis) and bacterial foot infections. This is connected with a favourable temperature and high moisture content inside the shoes, enhancing microbial growth [27]: A poor growth of yeasts *Candida albicans* and moderate growth of *Staphylococcus aureus* was observed under specimens of leather finished without essential oils. However, no growth of *Escherichia coli* was recorded [28], thus microbes in the raw skin go beyond the tanning process and therefore it is relevant to take note of the leather microbiome and their possible effect on human health. This can be done by adding effective fungicides and bacteriocides on processed leather with less effect on human health.

#### **3. Reported cases of beneficial microbes on humans from leather products**

 Micro-organisms with the symbiotic relationship with the skin occupy a wide range of skin niches and can protect it against invasion by harmful organisms. One such type of bacteria that is known to protect the skin is *Bacillus subtilis*. It produces bacitracin on the skin surface, a toxin that helps it in fighting with other intruding microbes [1, 2]. These skin microflora may also have a role in educating billions of T cells, making them ready to respond to similarly marked pathogen [3]. Most of the time in our lifetime, we share our bodies harmoniously with the 90 trillion or so microbes [29]. By simply taking or applying antibiotics, we could be disturbing the stable ecosystem in our body by killing not only disease-causing micro-organisms but also good bacteria, like *Lactobacillus acidophilus* which protects the body against pathogenic bacteria. A balanced co-existence between microbes and human bodies requires appropriate use of antibiotic and reserving the good role these organisms play in the animal and human health. Some resident microbes are known to protect animals against pathogens. Evidence attributed to this comes mainly from studies performed with germ-free animals, which were found to be extremely sensitive to infection and some died following the administration of a pathogen [30].

Microbes on the skin and other parts of the body have been known to protect it against environmental toxic materials, such as heavy metals, hydrazine, fungal, plant toxins, oxalic acid among others [30]. It is also speculated that changes in temperature, present problem to some animals that cannot use their skin to regulate their body temperature. This regards how to carry out cellular metabolism at both high and low temperatures. Some microbiotas can help solve this problem by providing enzymes optimised for different temperatures. On the other hand, an animal's microbial symbiotic partners may as well play a significant role in helping select the trait of endothermy. The constant high temperature of the surrounding environment speeds up bacterial fermentation by providing rapid and sustained energy input for the host. These benefits become apparent when comparing conventional to germ-free mammals, which sometimes require one-third more food to maintain the same body mass [30]. Some good bacteria inhibit fungal growth in parts of the skins. For, an example in the forearm of a human there are over 100 species of bacteria that keep the skin healthy. On average, it is reported that the skin supports about 1 trillion bacteria species. The most common among them are *Staphylococcus, Streptococcus*, and *Corynebacterium,* which metabolise sweat on skin surface to produce the bad odour. Most of these mentioned bacteria actually help to keep the skin healthy by competing with dangerous pathogens for nutrients and growth space. *Firmicutes* and *Bacteroides* are known to break down carbohydrates and make essential nutrients like vitamins K and B12 for the animal's body development. They also block out harmful bacteria from invading the skin.

#### *The Role of Leather Microbes in Human Health DOI: http://dx.doi.org/10.5772/intechopen.81125*

 Other evidence suggested by different authors, states that commensal skin microbes are necessary and sufficient for the generation of optimal skin immunity. This has been observed from germ-free mice in an experiment. The mice failed to mount an adequate immune response to *Leishmania* disease. Recolonisation of the mice gut with microbes was unable to restore cutaneous immune function to this animal, but exposing the skin of these mice to *S. epidermidis* alone was sufficient to restore the effect or T cell levels and rescue the immune deficiency from total collapse. These observations according to the writer were linked to IL-1 signalling, as germ-free mice showed significant decreases in cutaneous IL-1α production. The evidence adduced here suggests that communication between commensal microbes and skin-resident cells is important for proper tuning of the local inflammatory milieu [1, 2, 30]. The potential impacts of commensal microbiota from leather on the response and development of an effective immune environment on the human skin are still unclear and therefore require further studies.

 Fungi are also beneficial partners in symbiosis with the animal's skin [31]. This microbe has the ability to grow on vertebrate animal skins. Some fungi species can attack insects and nematodes in the skin and in the long run play an important role in keeping populations of these animals under control. Insect-attacking fungi are called "*Entomopathogens*," and they include a wide range of fungi in phyla *Ascomycota, Zygomycota*, and *Chytridiomycota*. Some of the best-known and most spectacular *Entomopathogens* among them belong to the *Ascomycota* genus *Ophiocordyceps* [31]. Beneficial microbes that are not mentioned here have other roles inside the animal's body. There are also some microbes with unknown roles in the skin of the animals yet they occur there abundantly. Some have been isolated but others are yet to be isolated and cultured. They make the study of leather microbiome necessary.

#### **4. Mechanism of microbes transfer from animal skins and leather products to humans**

 The human skin might also be affected by the microbes from the animal's skin with which they get into close contact [32]. Previous studies as reported by other authors on European populations have shown that the skin microbial communities of dog owners are closely similar to the microbial communities of their dogs than those of other dogs. The report goes on to confirm that close contact with dogs significantly influences the microbial communities on the human hand that touches them regularly [33, 34]. Research on animal owners in Madagascar in Africa found out the connection between human skin and animal skin microbes. As expected, the animal skin microbiota was established to be more similar to its owner's body parts [35]. Animal owner and non-owner body parts after comparison were found to be made up of similar proportions of *Proteobacteria*, *Actinobacteria, Bacteroidetes, Firmicutes* (the four dominant human skin bacterial phyla) and *Cyanobacteria*  [36]. In contrast, their animals were majorly dominated by *Proteobacteria* (88.5%). Animal owner's skins were found to have higher proportions of *Actinobacteria*  and *Firmicutes*. The authors further found out that contact with the animal might not really be a major driver of skin microbial communities on their owners. This is because, certain bacterial taxa may be better suited to colonising human skin than animal skin, perhaps based on differences attributed to factors such as hair, sweat glands, pH or host genetics [37]. These findings suggest that interactions within the shared environment of all humans, regardless of animal ownership, can homogenise the skin microbiome, but that different body sites may harbour distinct microbial communities due to dispersal from environmental microbes [37, 38].

 Animal hides and skins could also act as a mechanism for the transmission of bacteria and other microbes, due to its high content of moisture and nutrients (carbohydrates, fats, and proteins). These raw materials for making leather also contribute to the indoor environment of a tannery. The indoor environment inside the tanning industry has been associated with some human diseases attributed to biological agents. Conducted studies report that livestock and tannery workers have contracted diseases such as *Tetanus, Anthrax, Leptospirosis, 'Q' fever, Brucellosis, afta epizootic, Dermatosis and Micotoxicosis* due to infection and contamination of raw hide or skin, poor working conditions and to some extent processed leather. In addition, the above, genuses of fungi have also been reported in this environment, and they include species such as *Aspergillus niger* and *Penicillium glaucum*. Yeast genera that include *Rhodotorula*, *Cladosporium Torulopsis* have also been reported. Prolonged exposure of tannery workers to the tannery environment and their processed products has been closely linked with the development of allergies and asthma as well as the long-term exposure to fungi microbes. This ends up in the development of respiratory infections and other diseases [39]. For example, in Bangladesh, the common health problems diagnosed among the tannery workers were reported as shown in **Table 1**.

On the other hand, it would be interesting to determine if the above-mentioned taxa, are transient members of the human skin community as a result of temporary contact between the human body and this animal by-product, or it is due to longterm contact with animals and their products (and the shared environment) results in fundamental shifts in human skin communities that allow taxa that are typically considered animal and their products microbes to become residents [41]. When a beneficial microbe of animal skin is transferred to the human skin through the use of leather products, where there are a resident species of the same genera, what happens between the introduced species and indigenous microbes is still unknown. For example, *Bacillus subtilis* is known to protect the skin against other microbes.


#### **Table 1.**

*Prevalence of diseases including occupational dermatitis among tannery workers of Bangladesh (adapted from Mahamudul [40]).* 

*The Role of Leather Microbes in Human Health DOI: http://dx.doi.org/10.5772/intechopen.81125* 

What happens when the one from animal skin/leather product is introduced into the human skin which is occupied by resident human *Bacillus subtilis*?. This is still unclear and provides an area worth looking into in future studies of the leather microbiome. This is because it is not known whether they live mutually, commensally, compete or they kill one another to get or retain the space. Clear explanation about this interaction is now necessary considering the fact that leather plays a basic role in human daily life.

#### **5. Possible reported ways to hinder the transmission pathway of microbes to humans**

 The microorganisms grow on raw hides firstly because of their ability to hydrolyse the proteins present. This is due to their proteolysis degrading effect of the raw hide/skin substance [42]. In the literature, various authors have shown concern with halophilic micro-organisms and the problem of the colouration of cured hides/skins. The role of halophilic and non-halophilic bacteria producing or not producing coloured spots on salted hide/skin is still not yet clear, because the individual types can manifest themselves successively to a point that their individual hydrolytic effects are hidden from detection by various methods. Various bacterial species isolated from fresh calf skins are reported to have the ability to withstand a high level of salt (NaCI) concentrations (1.5–9% w/v) [42]. These isolated bacterial species included *Bacillus coli, Bacillus proteus, Bacillus megaterium, Bacillus mycoides, Bacillus subtilis, Staphylococcus albus, Staphylococcus aureus, Sarcina lutea* and *Micrococcus roseus*. *Bacillus subtilis* and *Bacillus mycoides* were found to survive in the dormant state at a high salt concentration (20% w/v) [42]. Bacteria called *Mesophiles*, such as *tuberculosis* known to be causing *Mycobacterium tuberculosis* can survive best at normal room temperature and are likely to thrive longer than cold-loving *Psychrophiles* or heat-loving *Thermophiles.* Other microbes do form exoskeleton-like spores as a defence mechanism, like the bacteria called *Staphylococcus aureus*. It is responsible for toxic shock syndrome and wound infections. The *Bacillus anthracis*, anthrax-causing bacteria, can also form spores and survive tens to hundreds of years [6]. The use of salt as a bacteriostat is to inhibit the growth of these microbes on the green hides and skin in curing premises.

 When converting skin into finished leather, collagen which is the basic fibre component must be protected since many characteristics of finished leather, particularly its durability, rely on collagen protein. Thus, bactericides with a broad spectrum are widely preferred in the main soaking process to stop bacterial attacks. However, fungi and bacteria displaying proteolytic and lipolytic activities at a remarkable level on raw hides and skins and in the pre-tanning floats should be taken into consideration and monitored. This is due to, the fact that these microbes are able to survive in extreme conditions [43]. A number of bacterial species such as *Bacillus sp*., *Pseudomonas sp*., *Alcaligenes sp., Escherichia coli*, and *Shewanella alga*  are reported to have Cr6+ detoxification capability due to the presence of reductases enzyme soluble in cytosol [44]. In *Pseudomonas maltophilia* and *Bacillus megaterium*, the Cr6+ reduction is associated with membrane cell fractions [16]. However, at present, it is still unclear whether the reduction of Cr5+ to Cr4+ and Cr4+ to Cr3+ is coordinated or enzymes regulated process. The NADH, NADPH, and electrons from the endogenous reservoir are suspected to be the electron donors in the Cr6+ reduction process. However, unlike Cr6+ reductases enzymes isolated from aerobes microbes, the Cr6+ reducing activities of anaerobes microbes are associated with their electron transfer systems ubiquitously catalysing the electron shuttle alone [16]. During the reduction reaction, the enzyme Cr6+ reductase (ChrR) transiently

reduces Cr6+ with a one-electron shuttle reaction to form Cr5+ followed by a twoelectron transfer to form Cr3+ [46]. Although a proportion of the Cr5+ intermediate is spontaneously reoxidised to generate reactive oxygen species (ROS), its reduction reaction through two-electron transfer catalysed by ChrR reduces the chances to produce harmful radicals which can harm the cell. Several facultative anaerobes such as *Pseudomonas dechromaticans, Pseudomonas chromatophila, Aeromonas chromatica, Mycobacterium spp, Geobacter metallireducens, Shewanella putrefaciens, Pantoea agglomerans*, and *Agrobacterium radiobacter* EPS-916 are also reported to catalyse the biotransformation change of Cr6+ to Cr3+ under anoxic conditions [45].

Biodeterioration is reported to be an important factor that can impair aesthetic, functional and other properties of leather and other biopolymers or organic materials and the products made from them globally. This process takes place particularly under conditions of high relative humidity that enable bacteria, actinomycetes fungi or other microbes to grow fast [15]. Biodeterioration in the leather industry has been mentioned to results from the activity of macro- and micro-organisms on raw hides and skins, during leather manufacture and also during storage of finished leathers and leather articles [20, 46, 47]. Because of its protein and lipids nature, leather provides a suitable substrate for many microorganisms. The biodeterioration process also happens on detanning (removal of chrome tannin on leather) effect and growth of *Penicillium spp*. The cross-link between collagen protein and chromium tanning agent is weakened during the biodeterioration reaction. It is speculated that protease enzymes that are produced by the *Penicillium spp* could be the degrading agent for chromium tanned leather. At the beginning of biodeterioration reaction, the *Penicillium spp* could be using the uncross-linked collagen protein as nourishment to grow and multiply, leading to the damaging of the collagen molecule. The *Penicillium spp* growth and multiplication makes tanning effect much weaker and susceptible. The detanned chromium leather becomes much easier for the *Penicillium spp* digesting enzymes and the biodeterioration begin slowly until the whole leather is affected completely [48].

In most cases, the *Pseudomonas spp* are normally present on the skin surface. Fur and skin layer might also contribute to the *Bacillus spp*. The presence of antibioticresistant plasmid harbouring *E.coli* has also been reported in leather and leather products [49]. *Staphylococcus aureus* generally has been present in epidermal and dermal layers of the animal's skin. These isolates were detected to have antigenic structures that enable them to resist antibiotics. The resistance development may be due to the nonspecific mechanism with gene regulation of plasmids and chromosomes, which may be heritable or transferable due to the presence of the resistance factor (R-factor) [49]. These structures enable the microbes to withstand extreme alkalinity and acidity in the tanning process; as such these microbes pose a real health hazard to the tannery workers.

 Various studies have been carried out in order to develop clean or cleaner technologies to reduce the pollution load during leather manufacturing processes. These clean and cleaner technologies are also known by other name as best available technologies (BAT) [50]. Initially, it was assumed that the replacement of hazardous chemicals with non-hazardous chemicals may provide suitable conditions for microbial growth because of the shift in pH concentration. The growth and survival of micro-organisms, particularly pathogenic bacteria related to health issues, at various stages of the leather manufacturing processes (both conventional and BAT) has been investigated using *Bacillus cereus, Pseudomonas aeruginosa,* and *Staphylococcus*. At the end of the study, no considerable differences were observed between the effect of the conventional and BAT leather making processes on these bacterial growths. This study confirmed one fundamental issue of interest and concern, that is, the ability of bacterial cells to recover and regenerate during

#### *The Role of Leather Microbes in Human Health DOI: http://dx.doi.org/10.5772/intechopen.81125*

leather manufacture [50]. This is an important point to note when dealing with processed leather and leather products and their relation to the health of tannery workers.

 Careful consideration is still necessary regarding pathogen-related health issues even though the bacterial (*Bacillus cereus, Pseudomonas aeruginosa*, and *Staphylococcus*) counts were found to be low in processed leather. This is because, the risk of bacterial infections in humans may depend on many other factors, such as the tannery environment, the leather making procedures and the personnel involved in leather making processes. There is a likelihood that pathogenic bacteria may still be present and caution is recommended when dealing with hides/skins and leather products at any stage. Growth and proliferation of fungi in the hide/ skin and leather products also still require investigation, as various studies have shown that leather production may provide suitable conditions for fungal growth as BAT studies reported here did not include fungal study [51]. In addition to the above mentioned, areas for further qualitative and quantitative analysis is required to determine the presence of microorganisms in the tannery based solid waste as well, such as sludge, the fleshing, shavings, hair, buffing dust, and trimmings which are generated during leather processing. This is due to the fact that these wastes are now being recycled into different products and used for different purposes by the general populace.

#### **6. Pathogenic microbes on humans and on the leather products**

Although the majority of the isolated microbial species are non-harmful and do not cause infections to humans, studies also show that some species in the genera *Bacillus, Staphylococcus, Pseudomonas, Klebsiella, Aspergillus,* and *Candida* are considered pathogens or potential pathogens [52]. These microbes and others associated with animal skin and leather product cause diseases in human. For example, *Escherichia coli* and *Enterobacter species* can cause urinary tract infection, wound infection and abscesses septicaemia. *Lactobacilli species* are a rare cause of septicaemia, endocarditis, and meningitis [52]. *Staphylococcus epidermidis, Staphylococcus aureus* is the most common microbes found on the human skin and nose. About 25% of healthy people in the world carry these bacteria, according to the Centre for Disease Control and Prevention (CDC). *Staphylococcus* bacteria coexist peacefully on our body. If a person with low immunity gets the infection from someone else's *Staphylococcus*, the bacteria can cause nasty skin infections, and pneumonia [52].

 *Klebsiella species* may cause urinary tract infection, respiratory infection, and septicaemia. *Klebsiella pneumoniae, Klebsiella oxytoca, Klebsiella granulomatis* bacteria are generally found in human intestines, where they generally exist peacefully with others. However, different types of the bacteria can spread in the body and cause infection in sick patients in hospital environment, including pneumonia, blood infections, skin infections, and meningitis. *Haemophilus influenza* bacteria was mistakenly believed to be the culprit behind flu virus outbreaks long ago when it was first discovered in 1892. While most strains do not cause disease in humans, the bacteria can cause respiratory tract and heart valve infections and sexually transmitted chancre sores in those with weakened immune systems [52, 49]. *Streptococcus mitis, Streptococcus salivarius, Streptococcus mutans, Streptococcus pneumonia, Streptococcus pyogenes* bacteria range greatly in their potential to cause disease and how they are spread in the environment. Group A of the *Streptococcus*, generally lives harmoniously in the throat or on the skin but can cause mild illnesses such as strep throat and skin infections. Group B of *Streptococcus* infections tend to be more severe and are more common in older or sick adults with the weak immune

system. Group B infections are reported to be the leading cause of meningitis and blood infections in newborn children.

*Neisseria gonorrhoeae, Neisseria meningitidis, Neisseria lactamica, Neisseria cinerea, Neisseria polysaccharea, Neisseria mucosa, Neisseria flavescens, Neisseria sicca, Neisseria subflava, Neisseria elongata, Neisseria gonorrhoeae* and *Neisseria meningitidis* are bacteria that live in humans. Only two *Neisseria spp*  causes disease. These types are most notoriously known for causing meningitis and gonorrhoeae, which thrive in mucous membranes and they are normally spread through sexual contact. *Neisseria* generally live in the upper respiratory tract and are not harmful to humans. *Bacteroides caccae, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides fragilis, Bacteroides merdae, Bacteroides ovatus, Bacteroides stercoris, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus* bacteria have a complicated relationship with humans [52, 49]. When they are isolated from the gut, they assist in breaking down food and synthesising nutrients and energy for the body to use. When they escape the intestines, they can cause deadly infections in the blood and even form abscesses all over the body which is normally seen on the skin as signs of infection.

 *Clostridium perfringens, Clostridium difficile, Clostridium tetani* (only transiently associated with humans, do not colonise the intestines) bacteria are commonly found in the soil and human intestines, and generally do not cause problems. A few strains of *clostridium* can produce potent toxins, including botulism, tetanus, and an irritation of the intestines and cause a mild to a lifethreatening illness called *Clostridium difficile*, which causes inflammation of the intestines. *Mycobacterium* bacteria is most notorious for causing severe illnesses such as tuberculosis, leprosy, and Hansen's disease, though most species of *Mycobacteria i*n nature are benign in humans, unless in cases of those who have weakened immune systems. The *Pseudomonas aeruginosa* microbe is extremely versatile and can live in a wide range of environments, including soil, water, animals, plants, sewage, and hospitals in addition to humans. It seldom makes healthy people sick, but more typically causes blood infections and pneumonia in those who are hospitalised or have weakened immune systems. *Mycoplasmas* are particularly tricky to detect, diagnose, and eradicate in the human body. Though *Mycobacteria* belong to the normal flora in humans, most species of *Mycobacteria*  are harmful and can cause respiratory and urinary tract infections [52, 49]. Thus microbes found in animal skins and are able to survive through the leather tanning process and reach human skin might cause diseases in people with weak immune system.

#### **7. Conclusion**

 The most common bacteria found growing on leather purses are *Micrococcus*  and *Staphylococcus* species each accounting for around two-thirds, followed by *Bacillus* (14%). *Micrococcus* was found to be more common on the men's purses, while *Bacillus* was found only on women's purses. In general, the study found out that the most common bacteria and fungus prevalence in leather are *Micrococcus*, *Bacillus, Staphylococcus, Aspergillus spp, Trichoderma* and *Penicillium spp*. Some are non-harmful and do not cause infections in humans. Other species within the genera of *Bacillus, Staphylococcus, Pseudomonas, Klebsiella, Aspergillus,* and *Candida*  are pathogens or potential pathogens; therefore, they need to be monitored and controlled in skin and leather products to avoid their cross transfer as they can spread diseases in human. Thus, further studies on "leather microbiome" are of the essence to human health and disease.

*The Role of Leather Microbes in Human Health DOI: http://dx.doi.org/10.5772/intechopen.81125* 

### **Acknowledgements**

I acknowledge God for giving me strength to write this piece of work and the support of my promoters.

### **Conflict of interest**

I don't have any conflict of interest in this work.

### **Author details**

Richard O. Oruko\*, John O. Odiyo and Joshua N. Edokpayi Department of Hydrology and Water Resources, University of Venda, Thohoyandou, South Africa

\*Address all correspondence to: richardoruko@gmail.com

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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**55**

**Chapter 4**

**Abstract**

infection.

**1. Introduction**

tions is required for proper diagnosis.

initial symptoms to the final diagnosis.

Overview

Extra Pulmonary Tuberculosis: An

*Mycobacterium tuberculosis* is the bacterium that as a single agent is known to cause the infection with the most morbidity and mortality around the world. It is known to cause pulmonary infection in immunocompetent patient, but its dissemination outside the lungs has been linked to a high degree of cellular immunosuppression as seen in the advance stages of human immunodeficiency virus infection, and after chemotherapy. Despite extensive research, screening, education, and continuous efforts to try to eradicate and control the infection, tuberculosis is still one of the most prevalent infections throughout the world. Even the cases of extra pulmonary dissemination are seen to have increased. Extra pulmonary tuberculous dissemination has a very variable presentation that depends on the organ involved. The diagnosis is difficult and many times a long time passes between diagnosis and initial presentation. In this chapter, we will review how tuberculosis infection presents when the bacilli invades any tissue outside the pulmonary parenchyma, what the literature recommends for the proper work up and diagnosis, and general treatment for major organ system

*Onix J. Cantres-Fonseca, William Rodriguez-Cintrón,* 

*Francisco Del Olmo-Arroyo and Stella Baez-Corujo*

**Keywords:** tuberculosis, extra pulmonary, infection, mycobacterium

Although it is well known that *Mycobacterium tuberculosis* can be pathologic to any organ system, its manifestations can be so variable that sometimes it becomes a challenge for the clinician to identify or even consider it as the cause of the patient's symptomatology. Most of the times, an extensive work up with invasive interven-

Extra pulmonary tuberculosis (EPTB), described this way when the tuberculous mycobacterium invades areas outside the pulmonary parenchyma, has nonspecific clinical findings developing insidiously [1] mimicking other noninfectious conditions [2]. It requires a high clinical suspicion and carries a lengthy period from the

Nevertheless, its presentation can be extremely acute causing a life threatening condition [1]. Clinical presentation will vary according to the organ system involved and more than one organ could be involved at the same time. The initial step in early identification is having knowledge of its findings in the proper clinical setting

#### **Chapter 4**

## Extra Pulmonary Tuberculosis: An Overview

*Onix J. Cantres-Fonseca, William Rodriguez-Cintrón, Francisco Del Olmo-Arroyo and Stella Baez-Corujo* 

#### **Abstract**

 *Mycobacterium tuberculosis* is the bacterium that as a single agent is known to cause the infection with the most morbidity and mortality around the world. It is known to cause pulmonary infection in immunocompetent patient, but its dissemination outside the lungs has been linked to a high degree of cellular immunosuppression as seen in the advance stages of human immunodeficiency virus infection, and after chemotherapy. Despite extensive research, screening, education, and continuous efforts to try to eradicate and control the infection, tuberculosis is still one of the most prevalent infections throughout the world. Even the cases of extra pulmonary dissemination are seen to have increased. Extra pulmonary tuberculous dissemination has a very variable presentation that depends on the organ involved. The diagnosis is difficult and many times a long time passes between diagnosis and initial presentation. In this chapter, we will review how tuberculosis infection presents when the bacilli invades any tissue outside the pulmonary parenchyma, what the literature recommends for the proper work up and diagnosis, and general treatment for major organ system infection.

**Keywords:** tuberculosis, extra pulmonary, infection, mycobacterium

#### **1. Introduction**

 Although it is well known that *Mycobacterium tuberculosis* can be pathologic to any organ system, its manifestations can be so variable that sometimes it becomes a challenge for the clinician to identify or even consider it as the cause of the patient's symptomatology. Most of the times, an extensive work up with invasive interventions is required for proper diagnosis.

 Extra pulmonary tuberculosis (EPTB), described this way when the tuberculous mycobacterium invades areas outside the pulmonary parenchyma, has nonspecific clinical findings developing insidiously [1] mimicking other noninfectious conditions [2]. It requires a high clinical suspicion and carries a lengthy period from the initial symptoms to the final diagnosis.

Nevertheless, its presentation can be extremely acute causing a life threatening condition [1]. Clinical presentation will vary according to the organ system involved and more than one organ could be involved at the same time. The initial step in early identification is having knowledge of its findings in the proper clinical setting

and including them within the differential diagnosis. Even though some patients do not have the expected risk factors, tuberculosis is identified as the culprit of symptoms associated with other conditions.

This illustrates the ample spectrum of extra-pulmonary tuberculosis manifestations. Vast medical knowledge helps the clinician to identify this condition in the adequate clinical scenario to pursue its diagnosis.

In this chapter, a review of the most important clinical manifestations of extrapulmonary tuberculosis will be discussed. It will also review the required work up and specific treatment for other organs involved.

#### **2. Epidemiology**

*Mycobacterium tuberculosis*, as a single infectious agent, causes more deaths than any other infection [3]. Outside infectious diseases, it is the ninth leading cause of death worldwide [3]. According to the World Health Organization (WHO) and the Global Tuberculosis report, in 2016, the largest incidence of tuberculosis occurred in areas of Korea and Africa [3]. In 2016, more than 10 millions of people were infected with tuberculosis around the world [3]. Active tuberculosis occurs in approximately 10% of the infected patients, involving lung parenchyma only in approximately 85% of subjects [7], but the incidence of other organ involvement varies widely in endemic and nonendemic areas.

 Worldwide, the incidence of extra-pulmonary involvement of tuberculosis occurs in approximately 17–52% of all cases reported [4]. In other publications, the incidence from reported cases varies from 15 to 40%, with approximately 3–3.5 cases per 100,000 of the population from 2002 to 2011 [5]. Although, the incidence has been stable or decreased in some areas, a report from 2003 to 2008 showed an increased worldwide incidence from 30.6 to 37.6% secondary to longer life expectancy of immunosuppressed patients due to better medical care [6]. In the United States, the incidence of EPTB increased from 15.7% of the cases in 1993 to 21.0% in 2006 [8]. Therefore, EPTB continues to be an important presentation within tuberculosis infectious spectrum.

 The demography of EPTB cases varies widely among documented case series. A review published in *Clinical Infectious Diseases* in 2009 [6] revealed that from 253,299 of tuberculosis cases reported in the USA from 1999 to 2006, 19% were extra pulmonary, while 8% were disseminated or concurrently pulmonary and EPTB. The mean age of this group was 44 years old, with a proportion of male to female almost one to one. Children (described in this population as less than 15 years old) with reported EPTB were approximately 6% of the cases. This same publication revealed predominance of genitourinary and bone and joint involvement in older patients (more than 60-year old), while children accounted for most of the cases of meningeal and lymphatic involvement.

#### **3. Organ involvement**

Tuberculosis can invade practically any organ. The proportions of organ involved in multiple publications suggest that most extra pulmonary tuberculous cases are seen with pleural, bone, and lymphatic involvement [6, 9]. In rare cases, the involvement can be localized to a specific organ [2], while 2–10% of the cases are reported to be disseminated within more than two organ systems [6, 9]. Most cases occur secondary to activation of previous pulmonary contagion.

#### **4. Risk factors**

Multiple populations with tuberculosis have been studied. In a case series described by García-Rodríguez et al., the mean age of patients with EPTB was higher than patients with pulmonary disease [6]. EPTB cases increased with the age, but the anatomical sites varied according to the age [6]. More cases of lymphatic, joint, and bone involvement were seen as patients become older. The female to male ratio varied according to the organ involvement, but in general, the male to female ratio was similar to other publications, which was one to one.

Although immunosuppression seen to be a risk factor for EPTB, a study published in *International Journal Tuberculosis Lung Disease* in 2009 suggested that diabetes mellitus was a risk factor for pulmonary tuberculosis, but not for EXPTB [10]. The protective mechanism for extra pulmonary dissemination of tuberculosis is known. The same study concluded that patients with end stage renal disease had a predisposition for EPTB. A possible mechanism that increases the risk for dissemination is a decrease cell-mediated immune response.

Other risk factors identified for extra-pulmonary dissemination include cirrhosis, malignancy, immunosuppressive drug use, alcoholism, HIV infection, chronic obstructive pulmonary disease (COPD), congestive heart failure, intravenous drug use, previous history of pulmonary tuberculosis, and history of cerebrovascular accident. There is not statistical analysis that linked all those causes as a direct risk factor for disseminated infection [10].

 Cell-mediated immunosuppression has been linked to the development of tuberculosis and an increased risk of dissemination. Multiple reports and publications have linked HIV infection to the risk of developing EPTB. Among HIV patients admitted due to tuberculosis, almost 50% have extra pulmonary involvement [11]. Concomitant pulmonary and multi-organ involvement is common. Low counts of CD4 lymphocytic cells, which are in charge of cellular immune response, have been reported to be directly proportional to systemic dissemination, increasing the incidence of central nervous system (CNS) infection. Those patients with CNS involvement have higher mortality. Therefore, HIV infection predispose patients to EPT and its severity increase when CD4 levels decline to 200 cell/mm3 .

#### **5. Pathophysiology**

Tuberculosis infection is caused by aerobic bacteria, *Mycobacterium tuberculosis*. Mycobacteria have a cell wall with considerable amount of a fatty acid, mycolic acid, attached to a peptidoglycan-bound polysaccharide arabinogalactan, which provide a strong barrier resistant to antibiotics and (natural) defense mechanisms [12]. Pulmonary tuberculosis is acquired throughout airborne droplets that get into lungs and lead to pulmonary infection. Most of the bacteria are trapped in alveolar macrophages and destroyed. The mechanism of macrophages engulfment includes complement cascade activation when protein C3 binds to the cell wall and enhances recognition of the mycobacteria by macrophages. Mycobacterium phagocytosis initiates a cascade of events that results in either successful control of the infection, followed by latent tuberculosis, or progression to active disease.

After macrophage engulfment, they present the mycobacteria to T cell lymphocytes, which generate the formation of granulomas around the organisms. Granulomas have low levels of nutrients that restrict mycobacteria growth and therefore control the infection. Those patients with decreased immune response fail to control the infection and develop primary pulmonary infection. In patients infected, droplets produced during coughing can further spread the infection to other patients. Dissemination of the mycobacteria to other organ systems can occur when the bacilli get into a blood vessel or throughout the lymphatic system.

 Reports suggest that most tuberculous empyemas and patients with vertebral bone involvement (Pott's disease) develop after the transport of tubercle bacilli from the pleural spaces to the parasternal and the para-aortic lymph nodes and the breakdown of caseous foci in these nodes [13]. These reports also explain investigations in which guinea pigs were injected with various doses of virulent tubercle bacilli inside their pleural cavity, developing granulomas in the liver, parasternal and para-aortic lymph nodes, spleen and kidneys, suggesting systemic dissemination. It all begins after the pleural space is invaded, disseminating to the thoracic lymph nodes and blood vessels, further seeding in distant organs.

#### **6. Tuberculosis and organ system involvement**

#### **6.1 Central nervous system**

 Central nervous system tuberculous involvement occurs in approximately 5–10% of extra pulmonary cases [14]. It is a rare disease within the whole tuberculosis spectrum. This presentation has the most dangerous and catastrophic consequences.

 Developing of CNS tuberculous infection has been linked to decreased cellular immune response as seen in HIV patients, malnutrition, alcoholism, malignancies, and the use of immunosuppressive agents [14]. Children and adolescents are more commonly involved with meningitis as the clinical presentation compared to adults (>15-year-old patients). In a study published in 2011, the mean age of patients with meningeal involvement is reported to be lower than those patients with infection in other organs such as lymphatic, bone and/or joint, and genitourinary [6].

Cases of EPTB are more common in older patients; however, a study from 2011 suggested that patients with ages less than 15 years old accounted for 5.4% of all TB patients. Although children were less likely to have EPTB, 13.8% of them presented as meningitis [6]. Peak of meningeal presentation was higher in patients younger than 24-year old. However, another study suggests that 40–70% of children with meningeal tuberculous involvement were exposed by older patients [15]. Risk factors related to meningitis by tuberculosis in children are similar to those related to infections in other sites, most cases related to some kind of immunosuppression. Median age of young patients with meningitis is approximately 4 y/o, and it is uncommon for children less than 6 months old to present with meningitis [15].

The most common clinical presentation of central nervous system involvement is meningitis. Most patients present with a history of nonspecific symptoms as malaise, anorexia, fatigue, fever, myalgia, and headache for approximately 2–8 weeks prior to the development of meningeal irritation [14]. In addition, neck rigidity and typical meningitis symptoms are more common in adults. These symptoms include depressed consciousness and nonspecific behavioral changes [14]. Tuberculosis can also cause focal nervous system deficits. Intracranial tuberculoma is the least common presentation. They are mass-like lesions that can be found in 1% of extra pulmonary patients with cerebral involvement and present with symptoms and signs of focal neurological deficit without the evidence of systemic disease [17]. Involvement of the spine occurs in less than 1% of TB patients, and it can be secondary to subjacent bone or soft tissue involvement [14]. Approximately 10% of patients with CNS tuberculosis have evidence of pulmonary tuberculosis [16].

#### *Extra Pulmonary Tuberculosis: An Overview DOI: http://dx.doi.org/10.5772/intechopen.81322*

 Diagnosis of intracranial mycobacterium tuberculosis infection requires cerebral spinal fluid (CSF) cultures or acid fast stains obtained by spinal tap or tissue biopsy. Rates of CSF culture positivity for clinically diagnosed cases range from 25 to 70% [14]. In some cases, large volume spinal tap is required for diagnosis. However, HIV patients usually require less amount of fluid for diagnosis. Drug sensitivity testing is important for appropriate treatment. CSF sensitivity for culture and smear staining decrease significantly after treatment has been started [14], for which rapid diagnosis is essential to warrant the best outcome.

 Polymerase chain reaction for *Mycobacterium tuberculosis* has also been used with variable results. Moreover, tuberculin skin tests and interferon gamma release assays could suggest exposure, but has limited utility for active disease diagnosis. Cerebral spinal fluid analysis for adenosine deaminase protein (ADA), an enzyme produced by lymphocytic proliferation differentiation during cell-mediated immunity, has also variable sensitivity for CNS infection. But standardized cutoffs have not been established. It has been used to predict CNS infection sequel that suggests poor outcomes in patients with higher values [14]. However, ADA levels in CNS can be high in other infections and noninfectious CNS pathologies. Therefore, correct diagnosis still requires CSF or tissue sample for AFB stains and cultures for mycobacterium.

Prompt therapy initiation with intravenous medications is extremely important for the treatment of tuberculous meningitis. First, line therapy for tuberculous CNS infection includes a combination of isoniazid, rifampicin, pyrazinamide, and ethambutol, which has to be taken daily. The recommended minimum duration is 10 months of therapy, which can be extended to 12 months if any interruption occurs during therapy. All medications have good hematoencephalic penetrance. On the other hand, monotherapy is not recommended due to the risk of developing an antimycobacterial therapy resistance, especially with isoniazid.

CNS lesions causing mass effect and hydrocephalus may require neurosurgical evaluation and cerebral decompression.

Systemic anti-inflammatory therapy with steroids should be started concomitantly (see **Table 1**). The use of anti-inflammatory medication has shown to decrease mortality without additional risk of adverse events [18]. Based on animal studies, the benefit of steroid therapy results from the reduction of the inflammatory process with a subsequent decrease in cerebral and spinal cord edema and brain pressure [18], with less disruptions in blood flow and cerebral perfusion.

 In view of this, early diagnosis and initiation of antituberculous therapy with systemic steroids are vital to decrease mortality and improve outcome in patient with CNS tuberculous infection.

#### **6.2 Thoracic extra pulmonary tuberculosis**

It is believed that the development of extra pulmonary manifestation starts after mycobacterium bacilli invade pleural cavity from subjacent pulmonary parenchyma and then migrates to the lymphatic system, blood vessels, and eventually to other organs outside the thoracic cavity. For this reason is important to rule out pulmonary parenchymal tuberculosis when a patient is suspected to have a pleural effusion secondary to pleural invasion. Manifestations of tuberculosis in the pleural cavity could present either as pleural effusion or empyema. Pneumothorax as a result to parenchymal cavitary lesion rupture can also be seen. All pleural tuberculous involvements can end up in pleural tissue fibrosis or fibrothorax.

Fluid accumulates in the pleural cavity as a consequence of a hypersensitivity reaction to bacilli mycobacterium in the pleural space. Pleural tuberculosis occurs approximately in 5% of patient with tuberculosis in USA and can reach as high a 30% of patients within high prevalence populations [19]. Tuberculous pleural


*\*Streptomycin can be added based in susceptibility.* 

*\*\*Therapy also can be based on susceptibility including Levofloxacin, Linezolid and Streptomycin.* 

#### **Table 1.**

*Extra pulmonary tuberculosis treatment.* 

effusions usually occur in the right side; these are small to moderate in size and are characterized as an exudate fluid. Fluid analysis is characterized with high protein levels (>5 g/dL), cell count around thousands, and lymphocytic predominance. It usually presents with more than 80% of lymphocytic predominance, and depending on the time of diagnosis, variable amounts of lymphocytes from 20 to 90% has been seen. In addition, low pH and low glucose levels can also be seen in pleural fluid analysis. Long standing effusions result in a highly acidic fluid. Lactate dehydrogenase enzyme (LDH) levels usually range above 500 IU/L [19].

 Adenosine deaminase (ADA) levels (see CNS involvement) are of particular utility in suspected tuberculous pleural effusions. The diagnostic use of ADA depends on its sensitivity and specificity and the regional prevalence of the infection. In a high prevalence population, an elevated ADA level (>40 U/L) is considered confirmatory with a clear indication for therapy. In low prevalence populations, a low ADA level (<40 U/L) has a high negative predictive value and therefore, rules out the diagnosis [19]. There are cases where ADA levels are not considered reliable, for example, in patients with pulmonary, pleural or hematologic malignancies, nontuberculous bacterial infections and also in those who underwent pleural procedures.

 Acid fast staining and culture test have limited diagnostic utility. Patients with pleural effusions of unknown etiology should be evaluated for a possible infectious

#### *Extra Pulmonary Tuberculosis: An Overview DOI: http://dx.doi.org/10.5772/intechopen.81322*

cause, including tuberculosis. This is essential in patients with history of TB exposure, immunosuppression (including HIV), and pleural effusions with nonspecific characteristics, and lymphocytic cell count predominance.

Acid-fast smears are almost always negative. Positive cultures for mycobacterium tuberculosis have been reported in 10–70% of the cases [19], and consequently pleural fluid culture analysis has a low diagnostic yield. Positive culture is directly proportional to the level of immunosuppression. In an HIV patient, the yield doubles (20%) compared to the immunocompetent patient (10%). It is more common to obtain a positive culture in a liquid media versus solid media [19]. Positive pleural fluid cultures are useful for drug therapy sensitivity and should be obtained in every case of suspected tuberculous pleural effusion.

Pleural biopsy is considered one of the best diagnostic methods when tuberculous pleurisy is suspected. Definite diagnosis is obtained if mycobacterial bacillus is detected in the smear, culture or pleural tissue biopsy. In the appropriate clinical setting, the presence of granuloma obtained after pleural biopsy is highly suggestive of tuberculous pleurisy and demands treatment.

 Percutaneous biopsy has a yield of almost 90% when guided by ultrasound [18]. When pleural biopsy is performed, the instruments and technique used varies, but the yield improves when at least six samples are taken from different quadrants [20]. More invasive procedures such as thoracoscopy and open surgical biopsies have good diagnostic yields. Access to these techniques is limited in areas of endemic tuberculosis, and for this reason, less invasive work up is the usual diagnostic approach. When a pleural effusion is suspected to be of tuberculosis origin, without evidence of pulmonary parenchymal involvement, a positive ADA in endemic areas is considered diagnostic. A low ADA level (<40) needs further work up including pleural biopsy. In low prevalence populations, a low ADA almost rules out tuberculosis and in these cases other etiologies must be considered [18].

Treatment for isolated pleural tuberculosis does not differ from pulmonary tuberculosis. Unless the effusion is characterized as an empyema, drainage is not required, and the effusion is expected to resolve by itself in weeks after commencement of treatment.

#### **6.3 Gastrointestinal tuberculosis (abdominal tuberculosis)**

Gastrointestinal tuberculosis (GI Tb) is relatively rare in the United States and is the sixth most common extrapulmonary location. Populations at risk include immigrants to the United States, the homeless, prisoners, residents of long-term care facilities, and the immunocompromised. The peritoneum and the ileocecal region are the most likely sites of infection and are involved in the majority of cases by hematogenous spread or through swallowing of infected sputum from primary pulmonary tuberculosis. Pulmonary tuberculosis is apparent in less than half of patients.

GI TB is a major health problem in many underdeveloped countries. In those with HIV infection, it is more present.

In those with pulmonary Tb, intestinal involvement was largely present before effective therapy was available.

However, approximately 20–25% of patients with GI TB have pulmonary TB. The ileum and colon are the common sites involved [21].

Other comorbidities associated with lower GI tract TB have been in other series type II diabetes mellitus (23%) and alcoholism (23%). Half of the stool cultures for *Mycobacterium tuberculosis* yields positive for it. This is similar to what is found with biopsy cultures of affected GI tract [22].

Treatment with 6 months antituberculous therapy has been found to be as effective as 9 months of therapy in patients with intestinal TB [23].

#### **6.4 Specific situations**

*Esophageal* Tb is the least common site of Tb in the GI tract [24]. *Stomach and duodenal* involvement by TB is rare because of (1) the high acidity of peptic secretions and (2) diminished amount of lymphoid tissue in the first part of the GI tract. Dyspepsia, diffuse abdominal pain, is frequent.

Clinical features of intestinal TB include abdominal pain, weight loss, anemia, and fever with night sweats. Patients may present with symptoms of obstruction, right sided pain [25].

Malabsorption may be caused by obstruction that leads to bacterial overgrowth, a variant of stagnant loop syndrome. Involvement of the mesenteric lymphatic system, known as tabes mesenterica, may retard chylomicron removal because of lymphatic obstruction and result in malabsorption.

The ileum is more commonly involved than the jejunum. Ileocecal involvement is seen in 80–90% of patients with GI TB. The latter is due to the abundance of lymphoid tissue in the distal ileum [26, 27].

If ascites is present, the measurement of ascitic fluid adenosine deaminase levels is reasonable. Laparoscopic biopsy samples from the peritoneum should be stained for acid-fast bacilli (AFB), and cultures should also be obtained with a reasonable yield [28, 29].

#### **6.5 Genitourinary tuberculosis**

Tuberculosis usually goes into the genitourinary system after reactivation of previous acquired disease. This is the second most common presentation of extra pulmonary disease, following lymphatic spread of infection [30]. Tuberculous bacilli infect renal and reproductive organs after they travel through the circulatory system. Genital involvement also occurs by cutaneous lesions during sexual contact or by contaminated instrumentation.

 Genitourinary involvement mostly occurs after reactivation of latent disease, and time to reactivation occurs years after primary infection. Cases reported usually involve older patients with a median age above 40 year old and mostly affects male patients [23]. The urinary tract is usually involved and it can manifest as a simple cystitis or pyelonephritis with or without hematuria and renal failure.

When renal function is affected, the patient has urinary tract obstruction or an interstitial nephritis. The prostate, seminal vesicles, and epididymis are rarely affected. Epididymis is the most common genital organ involved in men followed by prostate [30]. Testicles involvement is very rare. In women, fallopian tubes and uterus are the most common genital organs involved and can cause infertility in small percent of young women [30].

Diagnosis is done showing evidence of bacilli in stain or cultures in urine or tissue obtained from the genitourinary tract. Granulomas and acid-fast bacilli can also be seen in tissue specimens from kidneys and reproductive organs [31]. Treatment is usually the same as pulmonary tuberculosis, with approximately 6–8 months as the recommended duration of therapy.

#### **6.6 Skeletal tuberculosis**

Skeletal tuberculosis presents with certain variability. It is responsible about 10% of all cases of extrapulmonary tuberculosis in the United States of America, with a highest prevalence among those immigrants who come from endemic areas. The proportion is no different between those patients infected with HIV versus those not infected. The most common affected area is the spine, follow tuberculous

#### *Extra Pulmonary Tuberculosis: An Overview DOI: http://dx.doi.org/10.5772/intechopen.81322*

arthritis, and follow by extraspinal osteomyelitis. Young individuals are more likely to be affected in highly endemic are while adult patients are more frequently in low endemic together with a late presentation [32, 33].

 The associated pathogenesis resides in disease confinement at the bone and the synovial fluid. It results after seeding during primary infection. Cellular and adaptive response are responsible of disease containment until reactivation which related to immunity failing which can be seen in different settings including older age, renal failure, malnutrition, and acquired immune deficiencies. Skeletal involvement shows histopathological pattern of caseous exudative or granular. The first occurs more frequently in children and it is characterized by inflammatory changes, bone destruction, abscess, and sinus tract formation. The last is much slower and much less destructive. Any bone can be infected with tuberculosis. Clinical manifestations include spondylitis, arthritis, and osteomyelitis [33, 34].

 Tuberculous spondylitis (also known as Pott's disease) is the most common presentation. It is responsible for one half of the bone-related cases and most commonly affects the lower thorax and upper lumbar region. The infection starts at the anterior area of the vertebral joint and locally spreads to the anterior ligament after that it will affect the local vertebral body. Once the adjacent vertebra is affected, it proceeds to involve the intervertebral disk space with vertebral narrowing and further collapse. This finding may lead to distortion of the spinal canal anatomy and possible neurologic compromise. Although continuous spinal infection is uncommon, it has been documented [35]. Less than 40% of the patients presents with fever and weight loss. Symptoms include progressive local pain over the weeks with associated muscle spam and rigidity. The patient may present with an erect posture with associated short steps. Unfortunately, due to the lack of medical access on endemic regions, many of these patients will present with cord compression. Radiography changes are first appreciated in the anterior part of the vertebral body showing areas of demineralization and loss of margin contour. Findings of next vertebral involvement are common. Sclerotic changes persist but the rest of the vertebra remains without involvement [36]. Although the disk is commonly obliterated, collected data show that multiple sites and sparing of the disk are possible [37].

 Arthritis may occur as part of direct infectious process to the joint or due to an inflammatory response. The infectious process is monoarticular and may affect any joint but most commonly the hip. The symptoms progress from weeks to months and presents with chronic swelling, pain, and loss of function without erythema. Constitutional symptoms occur in less than 30% of the cases [38]. The joint presents with effusion and loss of function with associated granulomatous changes, such changes lead to distortion and deformity of the joint. Treatment may include total hip replacement if debridement and antituberculous treatment is given [39]. Prosthetic joints can also be affected but it is very rarely. While arthroplasty may have an adequate outcome, infections related to hardware may co-exist with other bacterial infections. The same is painful, and hardware needs to be removed. On the other hand, symmetrical polyarthritis may involve large and small joints without local evidence of active TB, despite the presence of military, pulmonary, or extrapulmonary manifestations of the disease. Poncet's disease, other name given to the condition, seems to be immune-mediated and related to HIV co-infection. The inflammation resolves after starting antitubercular treatment without evidence of joint destruction [40]. Phemister triad may be observed in this case. The same consists of juxta-articular osteopenia or osteoporosis, peripheral osseous erosions, and gradual narrowing of the joint space. Although there is also evidence of local swelling and bode destruction, there is a preservation of the cartilage space.

 Osteomyelitis may occur in any bone of the body, and it is more commonly insidious but the case has described acute and subacute onsets, which are very rare. Clinical scenarios may include suspected malignancies or metastasis, but those findings are due to lytic tubercular lesions. It presents in unusual areas such as symphysis pubis, elbow, and sacroiliac joint [41]. Small bones may be affected without evidence of active pulmonary disease [38]. Ribs and sternum may also be affected. The firs may be confused as a breast or chest wall mass. The second may occur after coronary bypass surgery due to previous mediastinal involvement or as primary focus [42]. Radiological evident is usually present at the time of clinical presentation. There is osteolytic changes with minimal or none inflammatory changes, periarticular osteopenia, soft tissue swelling, and minimal or periosteal elevation [43].

Musculoskeletal involvement may also be seen at the epidural space, as an extraspinal mass or psoas abscess. The presentation may cause cord compression, rib erosion, and sinus tracts to the groin, respectively.

 The diagnosis of musculoskeletal tuberculosis is challenging considering its indolent progression and clinical presentation. Caliceal suspicion is warrant and detail travel history and exposition in needed. In addition, although, a chest X-ray neither includes nor excludes the presence of extrapulmonary manifestation, and it may give a clue of current situation or evidence of previous infection. Other studies such as computer tomography, myelography, and MRI help to describe in detail joint and spinal cord involvement. Biopsy with microscopy and culture of the suspected or infected area is need for drug testing and identification of isolates. Synovial biopsy is needed in case of TB arthritis is considered. The fluid may be aspirate and verified but findings and usually nonspecific. In case of findings or with draining sinus, culture of the latter may help to identify the pathogen, although polymicrobial isolates and fungal results may be present and misleading [44].

 Treatment is very similar to pulmonary TB. However, the course of therapy relies in whether the drug regime includes rifampin or not. Data suggest that dose that include rifampin may be shorter and as equally as effective as longer treatments (6–9 vs. 9–12 months). Shorter courses such as 6 months may be suitable on those cases that involve radical surgical resections [45]. Also, randomized clinical trials show comparable results after 5 years of treatment on those patients who received isoniazid with rifampin for 6–9 months vs. those who received isoniazid with either paraminosalicylic acid or ethambutol. Sixteen surgeries are required in different settings such as chest wall abscess, spinal diseases with a kyphosis of more than 40°, and spinal disease with progressive neurological deficits while on treatment or just advance neurological deterioration. This would lead to different alternatives such as decompression, drainage, debridement, and hardware placement for spine stabilization [46].

#### **6.7 Cutaneous manifestations of tuberculosis**

Although uncommon, tuberculosis also has skin manifestations. The same have been documented since 1826 and occurs in 1–2% of the infected individuals. Cutaneous classification varies, and it depends not only on clinical appearance but also on the method of infection, predisposing factors, and pre-existing TB exposure. The bacterial load may be variable, the same may be easily or difficult to detect [47]. Mode of infection may be due to inoculation secondary to exogenous source, endogenous (continue infection), or hematogenous spread.

Exogenous inoculation can occur due to primary inoculation or due to tuberculosis verrucosa cutis (TBVC). Primary inoculation is rare and occurs after direct skin invasion of a previous nonsensitized patient. Children of endemic areas are more affected. However, surgical procedure with infected equipment, piercing, and tattoos has been identified as causals. The infection is clinically apparent by the fourth week. A painless brown papule or nodule shallow about 1 cm affecting the

#### *Extra Pulmonary Tuberculosis: An Overview DOI: http://dx.doi.org/10.5772/intechopen.81322*

face and extremities. The lesion progresses slowly, and regional painless lymphadenopathy develops. The same may cause sinus draining tracks following skin perforation. Diagnosis relies on the tissue sample, acid fast, and culture. If left untreated, the patient became sensitize to tuberculin test. Hematogenous spread is possible resulting military pattern [48].

On the other hand, TBVC occurs after direct inoculation in a patient who is already sensitized with TB. Children of endemic areas are at high risk and those who are occupationally related. In children, the buttocks and ankles are more commonly affected, while in adults, it occurs more frequently at the fingers and the dorsum of the hands. It also presents with red-brown painless but warty plaques that grows peripherally. Ulceration and regional lymphadenopathy is not common, it may co-exist with bacterial infection. Diagnose may be challenge. Culture form the lesion are usually negative, tuberculin test is positive, and interferon gamma assay may play a role in the diagnosis. Biopsy superficial dermal pseudoepitheliomatous hyperplasia with hyperkeratosis and microabscess in the dermis or pseudoepitheliomatous rete pegs. The upper and middle dermis shows inflammatory infiltrates of giant and epithelioid cells. Patient usually responds to anti-TB treatment. If left untreated, lesions may persist [49].

Cutaneous involvement may also be causes by contiguous spread presenting as Scrofuloderma, tuberculosis cutis orificialis, and lupus vulgaris. Scrofuloderma are painless red-brown nodules subcutaneously located most commonly at the axillar, neck, and groin areas. The infection occurs because of direct extension of the infection from deeps structures invading the skin. Cervical nodes are the most common site of infection. They tend to enlarge forming ulcers and sinus tracts and may follow a line lymphoid distribution. Although the infection has been related to *Mycobacterium tuberculosis*, it has been described in other in mycobacterial infections other than tuberculosis such as bovis and following BCG vaccination [49]. The lesion may be healed spontaneously, but it may take a long time to leave a scar. Lupus vulgaris may be developed in association to the later. Children, adolescents, and older adults are more commonly affected. Diagnosis is made by smear, culture, and biopsy. Tuberculin test is usually positive, and concomitant pulmonary disease is common [50].

 Tuberculosis cutis orificialis (TBCO) is a rare manifestation of characterized by painful ulcers with pseudomembranous fibrous base from a prior red-yellow nodule with associated inflammation. The lesion may be sited at the oral, nasal, or anogenital area. It affects middle age and older adults with advance immunodeficient disease (cellmediated). Most of these patients already have a progressive, pulmonary, gastrointestinal, or genitourinary advance TB disease. Tuberculin test is usually positive. Clinical course is usually poor leading to disseminated military TB. Diagnosis relies on biopsy smear and bacilli identification with the identification of them at the ulcer. The same is also associated with tubercular granulomas at the edge of the ulcer and deep dermis.

 Lupus vulgaris results as a manifestation of TB reactivation. Is a chronic manifestation that can occur by direct extension, lymphatics, or hematogenous spread? It occurs more frequently on females than males, and it is the most common for old TB skin manifestation in Europe. Despite this, it has a different distribution which varies with geographical location. For example, in western countries, the distribution is more common located at the head and neck areas, while in subtropical or tropical areas is more common at the lower extremities [49]. The skin lesion is red-brown papule that progresses into a nonpainful plaque. The same grows up to 10 cm developing areas of atrophy with associated central clearing. There are also variations of the lesion, where it can develop hypertrophy and ulcerations. It may also infect with other infections. As can be appreciated in other forms of granulomatous disease, lesion can have a yellow-brown contour with "apple jelly" appearance [49]. Diagnosis may be difficult, since it cannot be detected by culture or histopathology. PCR plays

 a role in the identification of the mycobacteria. Although some cases have described, *Mycobacterium bovis* has potential pathogen. Pathology will show tuberculoid granulomas with central caseated lesions at the dermal area. The epidermal area may reveal atrophy acanthosis, hyperkeratosis. The disease, also known as Lupus TB, requires the use of anti Tb treatment. If not, the size of the lesion progresses developing ulceration of the skin with loss of architecture. Also, progression to skin-related cancer, such as squamous cell carcinoma, has been documented [50].

Skin lesion may also result from hematogenous spread from primary site of infection leading to metastatic tuberculous abscess, acute military TB, or lupus vulgaris. The first, metastatic tuberculous abscess occurs after developing cellmediated immunodeficiency occurring in adults and malnourished children. The abscess may be single or multiple forms subcutaneous nontender nodules that progress to ulcer and sinus tract formation without lymphadenopathy [49, 51]. Any part of the skin may be affected more commonly the extremities. The metastatic infection usually confers a poor prognosis in the predispose individuals. Diagnosis is done after the findings of bacillus formation in culture, smears, or biopsies. Histopathological, there is evidence of ample skin necrosis, may show granulomas at the dermis. Unfortunately, tuberculin test results are variable [51].

Acute miliary TB is a rare manifestation that occurs more frequently in patients with deficient cell-mediated immunity such as infants and acquired immunodeficiency syndrome. Lesions are pinpoint red-bluish or purpuric papules with associated vesicles that furtherly become crusted. The lesion may resolve in the following weeks leaving hypopigmented scar like tissue. Skin biopsy plays a role in the diagnosis where mycobacteria are frequently identified. TST is usually negative [51].

Patient who have a higher immunity may develop hypersensitivity reaction manifestation as tuberculid. The lesions may be papulonecrotic, lichen scrofulosorum, and erythema induratum of Bazin (EIB). The identification of a tuberculid is supported after the following: presence of detectable infection such a TST and interferon gamma release assay, identification of granulomatous lesion in the skin, failure to identify *Mycobacterium tuberculosis* in cultures and stains, and noted, the resolution of the skin lesions after anti-Tb treatment.

Papulonecrotic tuberculid is the most common. It occurs more frequently in children and young adults. It is a dark violaceous papule that progress to pustular and necrosis. It is more commonly located in the face, neck, extremities extensor areas, and buttocks. It may be recurrent if left without treatment [51]. Constitutional symptoms occur prior the lesions and lymphadenitis can be appreciated [51]. The lesions may resolve alone leaving residual scars. Diagnosis is based on history of TB and evidence of wedge necrosis at the dermal and epidermal areas with granulomatous inflammation, mycobacterial DNA identification, and probable focus. TST is usually positive, and lesion resolves with anti-TB treatment.

Lichen scrofulosorum is rare and presents more frequently in children and young adult with previous infection at the lung, bone, lymph nodes, or intracranial. The lesion is small 1–5 mm red-brown -yellow commonly located at the truncal area [49, 51]. The lesions may resolve spontaneously without treatment. It does not leave a scar, and anti-TB treatment brings complete resolution. As other tuberculid, the diagnosis is based on clinical presentation, histopathologic findings (tuberculid granulomas at the upper dermis and tuber, glands, and hair follicles). TST is usually positive with negative mycobacterial culture.

 Panniculitis of the lower extremity (EIB) may be seen in patients with TB. The manifestation usually occurs in middle age young females. The lesion is tender, red, subcutaneously located at the posterior aspects of the leg. The nodules may progress forming draining ulcers. Its course is chronic and resolves alone leaving scars. Anti-TB treatment is recommended. If panniculitis is associated to TB, TST is *Extra Pulmonary Tuberculosis: An Overview DOI: http://dx.doi.org/10.5772/intechopen.81322* 

 often positive. Diagnosis is based on clinical history and histopathological findings. Mycobacterial DNA may be identified by PCR but not always. Biopsy needs to include subcutaneous fat in a wedge fashion. The sample should reveal lobular with or without septal panniculitis, poorly form granulomas, necrosis of the fat with mixed inflammatory cells. Vasculitis may also. Other treatment alternatives include colchicine, NSAID's, potassium iodide, dapsone, tetracyclines, and antimalarial. Other kind of tuberculid, similar to EIB, is the nodular pattern occurs at the same areas but the granulomatous findings occur at the dermal-subcutaneous fat junction without ulceration or evidence of panniculitis.

#### **7. Conclusions**

Tuberculosis can invade almost any organ through the lymphatic system and blood dissemination. The manifestations of extra pulmonary tuberculosis can be variable depending on the organ and the system involved. The diagnosis is made through a high suspicion in the predisposed populations, and many times, extensive diagnostic tests that usually involve cultures and/or biopsies of the infected tissue. This is one of the infectious affections with a greater range of presentations, capable of pretending to be other noninfectious diagnoses.

#### **Conflict of interest**

No conflict of interest.

#### **Author details**

Onix J. Cantres-Fonseca\*, William Rodriguez-Cintrón, Francisco Del Olmo-Arroyo and Stella Baez-Corujo Veterans Affairs Caribbean Health System, San Juan, Puerto Rico

\*Address all correspondence to: onixcantres@gmail.com

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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**70**

### *Edited by Nar Singh Chauhan*

Microbes are ubiquitous and have ecological interactions with almost all life forms. Likewise, humans invariably engage in host-microbial interactions that could induce short-term or long-term efects. Some of these long-term crossover interactions have allowed successful colonization of microbes within or on the human body, collectively known as the human microbiome or human microbiota. Te human microbiome is identifed as playing a key role in various physiological processes like digestion, immunity, defense, growth, and development. Any dysbiosis in the human microbiome structure could induce the onset of various metabolic or physiological disorders. Cumulatively, the human microbiome is considered as a virtual human organ that is essential for host survival. Additionally, short-term biological interactions of the host and microbes have exposed microbes to the human cellular system. Tis exposure could have allowed the microbes to invade human cells for their growth and reproductioninduced onset of various infectious diseases. Tis book incorporates a number of studies highlighting the role of microbes in human health and diseases.

Published in London, UK © 2019 IntechOpen © ChrisChrisW / iStock