Chapter 30 Mycobacterial infections
1. What is the classification system of mycobacteria?
Extensive taxonomic work has been done to classify the more than 60 species of organisms belonging to the genus Mycobacterium. In the 1950s, Runyon classified the atypical mycobacteria based on their rate of growth, ability to form pigment, and colony characteristics (Fig. 30-1). The Runyon classification may also include distinctions among obligate human pathogens requiring direct person-to-person transmission, facultative human pathogens found in the environment that are rarely responsible for direct person-to-person spread, and nonpathogens (Table 30-1).
2. What are the staining characteristics of mycobacteria?
Mycobacteria are aerobic, non–spore-forming, nonmotile bacilli. They do not stain readily, but their most useful staining characteristic is acid fastness. Acid fastness refers to the ability to retain carbol fuchsin dye after washing with acid or alcohol as a result of a high content of cell wall mycolic acids, fatty acids, and other lipids. The acid-fast stain is also called the Ziehl-Neelsen stain. Other staining methods include the Dieterle, Fite, hematoxylin-eosin, auramine-rhodamine, and phenolic acridine orange stains. Acid fastness is also shared by Nocardia, Rhodococcus, Legionella micdadei, Isospora, and Cryptosporidium.
| CLASSIFICATION | OBLIGATE HUMAN PATHOGEN | FACULTATIVE HUMAN PATHOGEN |
|---|---|---|
| Slow Growers | ||
| M. tuberculosis complex | ||
| M. tuberculosis | x | |
| M. bovis | x | |
| M. africanum | x | |
| M. mycoti | x | |
| Photochromogens (Runyon Group 1) Form Yellow-Orange or Rust Pigment with Light |
||
| M. kansasii | x | |
| M. marinum | x | |
| M. simiae complex (M. simiae, M. triplex, M. genavense, M. heidelbergense, and M. lentiflavum) | x | |
| Others include M. intermedium, and M. asiaticum | x | |
| Scotochromogens (Runyon Group 2) Form Light Yellow to Orange Pigment with and without Light |
||
| M. scrofulaceum | x | |
| M. szulgai | x | |
| Others include M. injectum, M. lentiflavum, M. gordonae | x | |
| Nonchromogens (Runyon Group 3) Unable to Form Pigment |
||
| M. avium-intracellulare complex (M. avium, M. intracellulare, and other unidentified species) | x | |
| M. haemophilum | x | |
| M. xenopi | x | |
| M. ulcerans | x | |
| Others include M. celatum, M. genavense, M. gastri, and M. malmoense | x | |
| Rapid Growers (Runyon Group 4) Growth within 7 Days |
||
| M. fortuitum | x | |
| M. abscessus | x | |
| M. chelonei ssp. chelonei, abscessus, unnamed subspecies | x | |
| Others include M. phlei, M. smegmatis, M. fredericksbergense | x | |
| Noncultivable Unable to Cultivate in Media |
||
| M. leprae | x | |
Data from Bhambri S, Bhambri A, Del Rosso JQ: Atypical mycobacterial cutaneous infections, Dermatol Clin 27(1):63–73, 2009.
5. What is tuberculosis?
Tuberculosis is a systemic infectious disease that can affect any organ system, including the skin. Only approximately 5% to 10% of infections lead to clinical disease. The lungs, however, are the most commonly involved organ. Cutaneous tuberculosis has a broad clinical spectrum depending on the route of infection, virulence of the organism, and immune status of the host (Table 30-2). Lupus vulgaris and scrofuloderma, although rare, are the two most common forms of cutaneous tuberculosis.
7. Explain the route of infection in cutaneous tuberculosis.
Cutaneous tuberculosis may be acquired by three possible routes. The first route is exogenous infection acquired from an outside source (primary-inoculation tuberculosis and tuberculosis verrucosa cutis). The second route of infection is endogenous spread. This can occur by contiguous spread (scrofuloderma) or by autoinoculation (periorificial tuberculosis) as organisms are passed from internal organ involvement. The final route is through hematogenous or lymphatic dissemination (lupus vulgaris, miliary tuberculosis, and gummas).
| CLASSIFICATION | PRIMARY INFECTION (NONIMMUNE HOST) | SECONDARY INFECTION (IMMUNE HOST) |
|---|---|---|
| Exogenous | ||
| Primary inoculation tuberculosis | x | |
| Tuberculosis verrucosa cutis | x | |
| Endogenous | ||
| Scrofuloderma | x | |
| Periorificial tuberculosis | x | |
| Hematogenous/lymphatic | ||
| Lupus vulgaris | x | |
| Acute miliary tuberculosis | x | |
| Gummas | x | |
Data from Semaan R, Traboulsi R, Kanj S: Primary mycobacterium tuberculosis complex cutaneous infection: report of two cases and literature review, Int J Infect Dis 12(5):472–477, 2008.
8. Who is at risk of acquiring tuberculosis?
In the United States, the incidence of tuberculosis was decreasing until 1985 when it reached its nadir. Since 1985, the incidence of tuberculosis has markedly increased. Crowded urban environments, immigration, poverty, homelessness, intravenous drug abuse, loss of tuberculosis control programs, increased use of immunosuppressive medications (e.g., TNF-α inhibitors), and, most importantly, the HIV epidemic account for the rising incidence. High-risk groups include the elderly, urban homeless, alcoholics, intravenous drug abusers, prison inmates, migrant farm workers, minorities, and immunosuppressed patients (with HIV or from iatrogenic causes).
9. Describe the histopathologic hallmark of tuberculosis.
The caseation granuloma (also known as tubercle) is the histopathologic hallmark of tuberculosis. This consists of giant cells and epithelioid cells and usually has varying amounts of caseation necrosis. This pattern can also be seen in other infections and is not pathognomonic. Acid-fast bacilli are usually easy to find in the early lesions, but there are very few bacilli once granulomas develop.
10. How can one acquire primary cutaneous tuberculosis?
Primary-inoculation tuberculosis occurs from direct inoculation of M. tuberculosis into the skin and includes the chancre at the site and affected regional lymph nodes. The organism cannot penetrate intact skin and requires a break in the skin, such as a minor cut or abrasion. Reports have also implicated tattooing, ear piercing, circumcision, mouth-to-mouth resuscitation, and needle-sticks. In some cases, there is no documented injury.
11. Describe the clinical manifestation of primary-inoculation cutaneous tuberculosis.
Primary tuberculosis may occur in any age group, but is most common in children up to 4 years of age and young adults. The face, mucous membranes (conjunctiva and oral mucosa), and lower extremity are the usual sites of infection. A tuberculous chancre develops 2 to 4 weeks after inoculation and presents as a painless, firm, red-brown papule/nodule, which slowly enlarges, eventually eroding to form a sharply demarcated ulcer (Fig. 30-2). Regional, hard, nonpainful lymphadenopathy occurs 3 to 8 weeks after infection. The combination of the tuberculous chancre and lymphadenopathy is analogous to the Ghon complex in the lungs. The purified protein derivative (PPD) may initially be negative and diagnosis is confirmed by culture.
12. What are the different types of cutaneous tuberculosis?
Tuberculosis of the skin can be divided into two categories: true cutaneous tuberculosis infections and tuberculid reactions. True cutaneous tuberculosis includes lupus vulgaris, tuberculosis verrucosa cutis, cutaneous miliary tuberculosis, cutaneous primary tuberculosis, and tuberculosis cutis orificialis (Fig. 30-3). A tuberculid refers to a cutaneous or mucosal lesion that represents an immunologic response to a previous infection of tuberculosis at a remote site. Special stains and culture of a tuberculid lesion are negative. Tuberculid reactions include lichen scrofulosorum, papulonecrotic tuberculid, and erythema induratum.
14. Is lupus vulgaris related to lupus erythematosus or lupus pernio?
No. Lupus erythematosus is an autoimmune connective tissue disease. Lupus pernio is a cutaneous manifestation of sarcoidosis that presents as a violaceous patch on the face. Lupus vulgaris is a form of cutaneous tuberculosis. The term lupus is used to depict erosion as if “gnawed by a wolf.” Vulgaris means common or ordinary. Both of these terms are used in a variety of unrelated diseases.
15. Describe the clinical manifestations of lupus vulgaris.
Lupus vulgaris is a chronic progressive form of cutaneous tuberculosis that originates from another site and involves the skin or mucous membranes via contiguous, lymphatic, or hematogenous spread. In 40% of patients, there is underlying lymphadenitis, and 10% to 20% have underlying pulmonary involvement. The primary skin lesion is an asymptomatic macule or papule that is brown-red in color and has a soft gelatinous consistency (Fig. 30-4A). Diascopy, a test where a glass slide is gently pressed against the skin lesion, may be helpful in diagnosing lupus vulgaris. Lupus vulgaris lesions have a characteristic “apple jelly” color with this technique. Squamous cell carcinoma arising in a longstanding lesion is the most serious complication (Fig. 30-4B).
16. Where and when does lupus vulgaris develop?
Lupus vulgaris most often affects patients in their second or third decade of life. The most common site of involvement is the head and neck and, in particular, the nose, cheek, and earlobe. There may be extension to involve the oral, nasal, or conjunctival mucosa. In the tropics, the buttocks and lower extremities are more often involved.
17. What is scrofuloderma?
Scrofuloderma is a form of cutaneous tuberculosis that originates in tuberculous lymph nodes, bones, joints, or epididymis and spreads directly to the overlying skin. The most common locations include the lateral neck and the parotid, submandibular, and supraclavicular areas. The skin lesion presents as a firm subcutaneous nodule. As the lesion matures, there is extensive necrosis leading to a soft, doughy consistency, ulceration with bluish margins, and formation of a sinus tract. Necrotic cheesy material may drain from sinus tracts (Fig. 30-5).
18. Name the vaccination against tuberculosis. What type of vaccination is it?
Bacillus Calmette-Guérin (BCG) is a live attenuated strain of Mycobacterium bovis. It was discovered in 1921, but has not been widely used in the United States, with the exception of a very small number of at-risk infants who cannot receive chemoprophylaxis. In third-world countries, the BCG vaccine is widely used. This vaccination is contraindicated in immunosuppressed individuals who are at risk of disseminated M. bovis infection. Intravesical BCG is also commonly used as treatment for bladder cancer, and there have been reports of cutaneous tuberculous lesions following this therapy.
Figure 30-3. Tuberculosis cutis orificialis. Erythematous eroded plaque of perianal area.
(Courtesy of James E. Fitzpatrick, MD.)
Figure 30-4. Lupus vulgaris. A, Red-brown plaque on nasal tip. B, Lupus vulgaris with squamous cell carcinoma.
19. What drugs are used in the treatment of tuberculosis?
Drugs used in the treatment of tuberculosis can be classified into first-line essential, first-line supplemental, and second-line antituberculous drugs. First-line essential chemotherapeutic agents include isoniazid, rifampin, and rifabutin. First-line supplemental chemotherapeutic agents include pyrazinamide and ethambutol. Second-line drugs include cycloserine, ethionamide, levofloxacin, moxifloxacin, gatifloxacin, p-aminosalicylic acid, streptomycin, amikacin/kanamycin, and capreomycin. Isoniazid is the cornerstone of therapy, and rifampin is the second major antituberculous drug. Currently, the Center for Disease Control (CDC) endorses a number of 6-month and 9-month protocols. The 6-month regimens include an intensive 2-month therapy with three to four agents followed by a 4-month therapy with isoniazid plus rifampin or rifapentine.
Available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm. Treatment of Tuberculosis Accessed December 13, 2009.
21. What factors have led to multidrug-resistant tuberculosis?
Multidrug-resistant tuberculosis (MDRTB) is defined as combined resistance to isoniazid and rifampin, and can be either primary or acquired. Primary MDRTB occurs in a person who has not previously been treated, whereas acquired MDRTB is a result of treatment failure. The main factors leading to MDRTB include patient noncompliance in drug therapy, inability or unwillingness to find adequate health care, and inappropriate treatment regimens. Homelessness, intravenous drug use, and HIV infection favor the spread of drug-resistant tuberculosis. Resistance is prevalent in Asia, South America, and Africa. In the United States, miniepidemics of drug resistance are centered in New York City, Miami, and Michigan. Spread to health care workers is a major concern. Treatment cure rates of up to 96% have been published in the medical literature, but this requires aggressive and often very complicated management of the disease.
22. Are there any special treatment considerations for cutaneous tuberculosis?
Treatment of cutaneous tuberculosis is the same as for systemic tuberculosis and consists of effective chemotherapeutic agents. Small lesions of lupus vulgaris or tuberculosis verrucosa cutis may be excised, but the treatment must also include standard antituberculous therapy. Surgical drainage of scrofuloderma may shorten the treatment course, and surgical intervention is necessary in any draining lesion.
Table 30-3. First-Line Antituberculous Agents and Major Side Effects
| DRUG | SIDE EFFECT | SPECIAL COMMENT |
|---|---|---|
| Isoniazid | Peripheral neuritis Hepatitis |
From pyridoxine deficiency Occurs with 1%–2%, increased risk with age >35 |
| Rifampin | Hepatitis Orange stain of secretions |
More common when given with isoniazid May permanently stain contact lenses |
| Rifabutin | Neutropenia Hepatitis Orange stain of secretions |
Occurs in HIV patients More common when given with isoniazid May permanently stain contact lenses |
| Rifapentine | Hepatitis Orange stain of secretions |
More common when give with isoniazid May permanently stain contact lenses |
| Pyrazinamide | Hyperuricemia | May precipitate gout |
| Ethambutol | Optic neuritis | Avoid in children under age 13 |
Data available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm. Accessed December 13, 2009.
Key Points: Mycobacterial Infections
1. Cutaneous tuberculosis has a broad clinical spectrum, depending on the route of infection, virulence of the organism, and immune status of the host. Lupus vulgaris and scrofuloderma, although rare, are the two most common forms of cutaneous tuberculosis.
2. Caseation granuloma (also known as tubercle) is the histopathologic hallmark of tuberculosis, although it can also be seen in other infections and is not pathognomonic.
3. Mycobacterium tuberculosis can be diagnosed using acid-fast bacilli (AFB) stains, culture, polymerase chain reaction (PCR), or interferon-gamma release assay (IGRA).
23. What is the mechanism of action of TNF-α in tuberculosis?
TNF-α mediates host defense against infection. It is a key player in granuloma formation and containment of M. tuberculosis organisms. TNF-α inhibitors (etanercept, adalimumab, and infliximab) have been associated with reactivation of tuberculosis. Because of this risk, patients must be screened for tuberculosis prior to beginning treatment with a TNF-α inhibitor. If the PPD is positive, but the chest x-ray is negative, the patient may still receive the TNF-α inhibitor after starting antitubercular treatment for latent tuberculosis. The preferred regimen is 6 to 9 months of isoniazid. However, the risk of developing active tuberculosis is not obviated, and there have been reports of this despite an adequate course of isoniazid.
24. Describe the pathogenesis of the atypical mycobacteria.
Atypical mycobacteria (also known as nontuberculous mycobacteria, or NTM) are ubiquitous and are found in soil, water, and domestic and wild animals. Tap water is the major reservoir for the atypical mycobacteria that cause human disease. Because they are found everywhere, isolation of these organisms does not necessarily constitute proof of disease. In contrast to M. tuberculosis, they are not transmitted from person to person. Immunosuppression, organ damage, Mohs micrographic surgery, cutaneous surgery, punch biopsy, acupuncture, mesotherapy, injections, cardiothoracic surgery, breast reconstruction, facial plastic surgery, laser resurfacing, liposuction, body piercing, pedicures, tattoos, or minor cuts and abrasions are some of the clinical settings in which these organisms can cause disease. The presentation of these infections is quite variable, leading to frequently missed diagnoses. Depending on geographic location, atypical mycobacteria may account for 0.5% to 30% of all mycobacterial infections.
25. How is the diagnosis of atypical mycobacteria made?
Often the diagnosis is delayed because of the varied clinical and histopathologic findings. After inoculation, there is an incubation period of 1 to 29 weeks. Classically, this is followed by an eruption of painful nodules that increase to 2 to 5 cm in size, and which then drain purulent fluid for 7 to 14 days before forming a scar over 1-month period. Other skin lesions have been reported including folliculitis, furuncles, abscesses, cellulitis, nodules, draining lesions, ulcers, and fistulae. Granulomatous infiltrate, diffuse lymphohistiocytic infiltrate, mixed inflammatory infiltrate, granulomas rheumatoid nodules, abscesses, panniculitis, and folliculitis have been observed in biopsy specimens. Staining for acid-fast bacteria with Fite or auramine-rhodamine is often unrevealing. Thus the current gold standard is skin biopsy for tissue culture followed DNA sequencing.
26. What is a “swimming pool granuloma”?
It is an inoculation caused by Mycobacterium marinum, although, very rarely, it can be caused by Mycobacterium gordonae. M. marinum is ubiquitous in aquatic environments, including both fresh and salt water. The organism is inoculated into the skin through small cuts or abrasions while swimming or cleaning aquariums. Following an incubation period of 2 to 3 weeks (1 week to 2 months in some instances), a small violaceous papule develops at the site of inoculation. The lesion gradually enlarges into a dark red to violaceous plaque. A sporotrichoid pattern may be seen with violaceous nodules along the afferent lymphatics (Fig. 30-6A,B). The most common sites include hands, feet, elbows, and knees (sites prone to trauma). The diagnosis of cutaneous M. marinum infection is mainly clinical, with supporting evidence from histologic features and the response to therapy (Fig. 30-6C). The lesions typically heal spontaneously but may disseminate. This infection may respond to multiple single and combination antibiotic regimens.
27. What is a Buruli ulcer?
Buruli ulcer, caused by Mycobacterium ulcerans, is another of the inoculation mycobacterioses and is the third most common mycobacterial disease in immunocompetent individuals. It occurs in warm tropical climates, most notably Africa, Australia, and Mexico. The organism is inoculated into the skin through minor cuts, most commonly on the extensor surface of the extremities. Over a period of 4 to 6 weeks, a painless subcutaneous swelling develops; it may or may not be pruritic. The swelling then ulcerates and has a necrotic center, undermined borders, and can attain the size of an entire limb. Treatment is primarily surgical.
28. Describe the clinical manifestations of Mycobacterium avium-intracellulare complex (MAC) in both non-AIDS and AIDS patients.
Mycobacterium avium complex (MAC) includes M. avium, M. intracellulare, and other unidentified species, although it has recently become clear that M. avium is the most common cause. These organisms have gained importance with the epidemic of HIV infection. HIV-negative persons most commonly present with pulmonary involvement. Cutaneous disease is rare but may occur as a manifestation of primary intracutaneous inoculation or disseminated disease. The cutaneous lesions are quite variable and include ulcers, abscesses, deep nodules, or inflammatory plaques (Fig. 30-7). Eighty percent to 90% of childhood lymphadenitis is caused by MAC. AIDS patients with MAC generally present with widely disseminated disease (pulmonary, lymph node, gastrointestinal tract, bone). Isolated cutaneous disease is unusual but reported.
29. Which atypical mycobacteria are associated with mesotherapy?
Mesotherapy is the microinjection of drugs into the dermis. It has a variety of applications and despite the dearth of scientific data, is popular in Europe and South America as a procedure to reduce fat and cellulite and to perform body contouring. It is also offered in the United States. Most often the service is delivered in nonmedical settings under nonsterile conditions. A number of cases have been reported in the literature describing infection with rapidly growing mycobacteria following mesotherapy. The organisms include M. chelonae, M. fredericksbergense, M. abscessus, and M. fortuitum.
30. Which atypical mycobacteria are associated with tattoos?
Tattoo-associated infections have been described secondary to M. chelonae. Numerous patients have been reported in the literature with pruritic papules and pustules restricted to the gray parts of their tattoos. The gray wash was prepared by dilution of black pigment with tap water. Treatment with clarithromycin, azithromycin, tobramycin, or macrolide antibiotics resulted in a favorable outcome. Similarly, outbreaks of furunculosis from contaminated tap water whirlpool baths in nail salons have also been associated with M. chelonae and M. fortuitum (Fig. 30-8). Thirty-four patients with cutaneous abscesses following liposuction performed by a single physician were found to be infections of M. chelonae. The tap water in the office was the source.
31. Which atypical mycobacteria have been associated with soft tissue fillers?
In 2002 there were two cases of M. abscessus infection following the injection of soft tissue filler. Both patients were injected with Hyacell, a product not approved by the FDA but available in South America. It had been brought illegally into the United States and was administered by an individual posing as a physician. Hyacell is a mixture of hyaluronic acid, zinc, selenium, vanadium, and unspecified “embryonic extracts.” The patients developed tender nodules and were treated with resolution using clarithromycin and prednisone.
Cohen JL: Understanding, avoiding, and managing dermal filler complications, Dermatol Surg 34(Suppl 1):S92–S99, 2008.
32. How are infections with rapidly growing mycobacteria managed?
Surgical removal can be used in patients with a limited number of lesions. Antibiotics are added in immunocompromised patients or those with numerous lesions. M. chelonae has the greatest antibiotic resistance but is usually susceptible to tobramycin, clarithromycin, and linezolid. In vitro testing has also shown the efficacy of tigeycline and amikacin. Two to four months of antibiotics is recommended in localized disease and 6 months in disseminated cutaneous disease, but the optimal length of therapy is not clear. Testing for susceptibilities is advised before treatment begins in clinically significant isolates, and if treatment fails or there is a relapse. While waiting for susceptibilities results, clarithryomycin and azithromycin are useful oral agents for M. chelonae.
33. What are some of the key features of Mycobacterium kansasii?
M. kansasii is a photochromogenic acid-fast bacillus. It is found worldwide, including in the U.S.—particularly in the Southwest and the Midwest. The most common presentation is a pulmonary infection resembling tuberculosis, typically in older men with chronic obstructive pulmonary disease. Cutaneous presentation is heterogenous and includes an ulcer with sporotrichoid spread or cellulitis. It has a predilection for HIV-infected individuals (Fig. 30-9). In HIV-infected individuals, almost all colonized patients have disease and require treatment with ethambutol or rifampin.
