Chronic Infections

Guidelines for Specimen Collection and Handling

The successful identification of a specific pathogen often depends on collection methods, transportation process, and laboratory algorithms suitable for various organisms and samples. The specimen must be kept moist and transported rapidly. In general, the more quickly a specimen is planted onto an appropriate medium, the better are the chances for isolating bacterial pathogens. For ideal fungal cultures, specimens should be transported to the microbiology laboratory within 1 hour of collection. If a delay is anticipated, the specimen should be refrigerated until prompt next day delivery can be ensured. A sterile container, securely covered, is adequate; bacteriostatic saline or formalin should not be used for biopsy specimen considered for microbiology. Biopsied tissue or pus is better as a specimen than swabs for routine anaerobic, mycobacterial, and fungal cultures.

The suspected pathogen must always be communicated to the microbiologist personally and in writing if other than routine bacteria are suspected (e.g., Nocardia, Actinomyces, M. marinum, M. ulcerans, Sporothrix, Bartonella ). This facilitates the microbiologist’s choice of the best incubation medium, temperature, and period. Because there are many pathogen-specific paradigms for collection–transportation procedures, it is recommended that the surgeon seek advice from the laboratory microbiologist when in doubt about a particular chronic infection. It is absolutely essential that the microbiology laboratory be informed of the site of origin of the sample to be cultured, chronicity of the infection, and possible infectious agents suspected. This information determines the selection of culture medium, the temperature of incubation, and the length of time to culture.

Swabs of superficial ulcers of the skin and from surface of a sinus tract or from open abscesses commonly yield a host of mixed bacterial flora and often do not reflect the organism’s true infectious significance. For such infections, every effort should be made to biopsy tissue from the deeper aspects of the lesion or from the margins where the organisms are actively spreading. An adequate quantity of material should be obtained. At least 1 mL of fluid or a 1-g piece of tissue should be obtained for bacterial identification.

For mycobacterial identification, 10 mL of fluid or a tissue as large as possible should be obtained to compensate for the “paucibacillary” nature of the hand infection. For example, swabs are not adequate to detect the sparse organisms of tuberculous and fungal infections. Characteristically, chronic lesions contain few organisms, so the swab is likely to obtain much serum and few organisms. To recover the most bacteria, mycobacteria, and fungi, a swab should never be submitted in lieu of curetting, biopsy material, or synovial fluid.

Tissue biopsy is more likely to show the infecting organisms than pus or necrotic detritus. If a swab is used, the patient’s interests are best served by vigorous rather than gentle application of the swab to the target tissue. Biopsy from the undermined edge of an ulcer is far superior to a swab culture from the surface. Open biopsy is better than fine needle aspiration biopsy, punch biopsy, or superficial curettage of infected tissue. For meaningful culture results, laboratories prefer surgically obtained tissue samples, aspirates of closed abscesses, or a small amount of pus. Organism concentrations in synovial fluids and pus may be low, so as much fluid as possible should be obtained whenever mycetoma, mycobacterial, or fungal infection is a serious consideration. Specimens for smear and culture should be collected and transported in closed, leakproof, sterile containers.

Organisms are not uniformly distributed in infected tissue; thus several parts of the lesion should be sampled for smears and cultures to find the infecting organism. Impression smears made by gently pressing a freshly cut surface of the tissue onto a slide increases the chance of organism identification and should be requested from the microbiology laboratory in addition to routine ground tissue smears. This is because tissue impression smears are easier to read and interpret than those made from material that has been ground or macerated. Gram stains, calcofluor-white, or potassium hydroxide (KOH) stains for fungi, and acid-fast stains for mycobacteria, can also be done on slide impression smears.

If results prove negative but signs and symptoms indicate otherwise, repetition of biopsy, smears, and cultures may be necessary. If antibiotic therapy has been initiated, a direct smear may be the only available guide to the etiology because growth may be inhibited. After biopsy, the tissue specimen is immediately bisected: Half of it is sent to the pathologist in formalin, and the other half is sent promptly to the microbiologist for smears and cultures in a sterile container without formalin because it kills organisms.

An “eight-pack” tissue culture is sent to the microbiology laboratory for diagnosis ( Box 3.1 ). The first three packs are sent immediately for staining: gram stain for bacteria, acid-fast stain for mycobacteria, and KOH or stains for fungi (see Box 3.1 ). The next five packs are for cultures: two for aerobic and anaerobic bacteria, two for typical and atypical mycobacteria, and one for fungus. M. marinum, M. haemophilum, M. ulcerans, and S. schenckii grow best at 30°C. The rest of the mycobacteria grow best at 37°C; only one, M. xenopi, grows best at 42°C.

The microbiologist needs to know that the specimen is from a chronic lesion so that it can be incubated at an appropriate temperature. The microbiologist also should get the tissue fluid (i.e., pus, synovial fluid, serosanguineous exudate), whenever available, for eight-pack smears and cultures. The laboratory must know which antimicrobial agents, if any, the patient is taking. Whenever possible, the specimen is obtained before intraoperative antimicrobial agents are administered. A sterile tube with a tight-fitting cap is adequate for transporting bodily fluids. A sterile bottle or a jar is used to transport tissue specimens.

Tissue should be promptly forwarded to the laboratory. For chronic and unusual lesions, more often than not, we deliver the specimen to the microbiologist. This gives us an opportunity to communicate clinical history about the patient and tell the pathologist or microbiologist which organisms we are looking for. Fastidious organisms may not survive storage. Pus, fluid, and tissue should be placed into a transport vial in which anaerobes can survive for several hours in case the specimen is not delivered to the laboratory promptly. A simple way to collect and transport a fluid specimen, especially for anaerobes, is to aspirate at least 1 mL of it (pus, synovium) with a needle into a syringe, discharge any residual air at the top of the fluid, and seal off the syringe by bending the needle over itself and pinching the bend with a clamp. It is important not to leave any air in the needle before sealing it.

Histoplasma capsulatum, Cryptococcus neoformans, M. bovis, M. avium, Nocardia, and Bartonella may take more than 6 weeks to grow, and it is imperative to request that the microbiology laboratory not discard the cultures for at least 4 weeks. M. ulcerans and M. malmoense may take 12 weeks to grow, so to cover all the organisms in a chronic infection, we request that the microbiologist not discard the cultures for 12 weeks and to notify us as soon as growth is positive. It is a good idea to seek help from an infectious disease specialist who can closely follow the growth plates in the laboratory. In the care of immunocompromised patients or difficult diagnostic problems, numerous cultures or tests are often requested on the same specimen, for which there may be an inadequate quantity. The clinician should prioritize the test requests for the laboratory based on the highest clinical suspicions.

Four laboratory tests are used for identification of bacteria and mycobacteria: (1) direct visualization of the organism by staining, (2) detection of pathogenic-specific antigens and antibodies, (3) cultures in growth media, and (4) nucleic acid (DNA and RNA) amplification techniques. The fourth test is new and not widely available but is especially useful for diagnosing stains, cultures, and serology tests and is very rapid.

Direct Visualization of the Organism by Staining

Gram staining is often the first step used by the hospital microbiology laboratory to identify an unknown bacterium from a clinical specimen. Gram stain differentiates between organisms with thick peptidoglycan cell walls (gram-positive) and those with thin peptidoglycan cell walls that can be dissolved with acetone (gram-negative). The sensitivity is such that >10 ⁴ bacteria per mL is necessary for detection.

An acid-fast stain identifies organisms that retain red carbol fuchsin dye after washing with an acid-alcohol (i.e., “acid fast”). Ziehl-Neelsen and Kinyoun stains are carbol fuchsin-based and stain mycobacteria red. However, fluorescent stains are more sensitive for detection of mycobacteria in direct specimens. The organisms stain brightly and can be clearly distinguished from background material. Slides stained with a fluorescent dye can be examined reliably with an objective lens of lower magnification (×25) than the oil immersion lens (×100) required for carbol fuchsin-stained smears; in addition, reading slides is faster and more reliable. This stain is preferred by the Centers for Disease Control and Prevention (CDC). Modification of an acid-fast stain also allows detection of Actinomyces, Nocardia, and other weakly acid-fast organisms.

It may be difficult to isolate H. capsulatum from clinical specimens. It is revealed in the biopsy tissue if Grocott silver stain is specified. India ink preparation is diagnostic for cryptococcosis and should be requested in patients exposed to pigeons. Identification of viruses require more sophisticated tools that may include electron microscopy, cryo-electron microscopy, cryo-electron tomography, x-ray crystallography, and nuclear magnetic resonance spectroscopy. Jacques Dubochel, Joachim Frank, and Richard Henderson were awarded Nobel prize for “developing cryo-electron microscopy for the high-resolution structure determination of biomolecules in solution,” which enabled three-dimensional imaging of DNA and RNA viruses.

Detection of Pathogen-Specific Antigens and Antibodies (Serology)

Biochemical methods are used to detect the antigens of newer mycobacterial species from cultures. Detection of cryptococcal polysaccharide antigen in serum is the most reliable for diagnosis of cryptococcosis. A high cryptococcal antigen titer in the purulent discharge from a cryptococcal skin ulcer confirms the diagnosis. An antigen test can help in diagnosis of histoplasmosis and gauge the efficacy of antifungal therapy. Testing for the presence of antibody has been successfully used for diagnosis of coccidioidomycosis. Measurement of serum antibody (i.e., immunoglobulin [Ig]G or IgM) provides an indirect marker for past or current infection with a specific pathogen.

Detection of Specific Microbial Nucleotide Sequences

Nucleic acid amplification technology (i.e., detection and quantitation of specific DNA and RNA base sequences in clinical specimens) has gained widespread use and has become a powerful tool for rapid diagnosis of viral, bacterial, mycobacterial, fungal, and parasitic infections. The use of nucleic acid tests generally involves lysis of infected cells and denaturation of DNA or RNA to render it single-stranded. Probes, that is, primer sequences complementary to pathogen-specific base sequences, then detect the pathogen-specific sequences. Use of nucleic acid polymerase chain reaction (PCR) analysis allows very rapid DNA sequence analysis and direct identification of M. tuberculosis, NTM, and fungal infections in clinical specimens. PCR can detect <10 organisms/mL in a clinical specimen, compared with 100 for cultures and the 10,000 necessary for a positive smear.

PCR analysis provides a useful method when a smear and culture are negative in the presence of a clinical presentation of TB. The test is generally accessible but is skill-intense, expensive, and done at limited laboratories. The potential for nucleic acid amplification testing (i.e., PCR) to enhance patient care is greatest when suspicion of TB is moderate to high and specimen smears are acid-fast bacillus negative. This holds true for other infections also. At least 2 g of tissue are necessary to do this test. The tissue should be set aside and preserved in 70% alcohol for later processing in case conventional smear and culture tests prove negative.

DNA probes are used with organisms grown in culture as well as directly on patient specimens. The procedure can be performed, and the organism identified, within a matter of hours from the time an infection is suspected while conventional cultures may take days or weeks.

Organism Isolation in Culture and Drug-Susceptibility Testing

Several quantitative studies have shown that a minimum of 10,000 bacilli/mL of specimen is necessary to detect bacteria in stained smears. When host immunity is high and bacterial virulence is low, infected tissue may have far less organisms per milliliter. In such cases, acid-fast staining may be negative. In contrast, <100 organisms are necessary to grow in culture. When investigating chronic infections, tissue samples should be cultured at least on blood agar, Lowenstein-Jensen medium, and a Sabouraud glucose agar. These three media should allow growth of most bacteria, mycobacteria, and fungi.

It is important that the clinician notify the laboratory if a pathogen with specific growth requirements is suspected so that special culturing media can be used. The excised tissue should be sent for cultures at three temperatures: M. marinum, M. chelonae, M. hemophilum, and Sporothrix schenckii grow best at 30°C; M. xenopi at 42°C; and the rest at 37°C. M. avium, M. fortuitum, M. terrae, and M. chelonae require prolonged incubation, and some require special media— M. hemophilum grows only in a hemoglobin-reinforced medium, and M. malmoense requires a pyruvate-containing medium. Pus from septic tenosynovitis may yield profuse growth of Actinobacillus actinomycetemcomitans if grown in the presence of CO ₂ . Otherwise, it is difficult to grow and identify this organism. Actinomyces spp. and Nocardia spp. grow only in anaerobic media.

M. haemophilum grows best in a selective agar medium enriched with hemoglobin. A major improvement in mycobacteriology has been the development of commercial broth systems that allow for rapid growth and detection of mycobacteria within 1 to 3 weeks, compared with solid media in which growth takes 3 to 8 weeks. Drug-susceptibility tests are performed on initial isolates from all patients with suspected TB to identify what should be an effective drug regimen. To generate rapid testing and faster turnaround time for better patient management, the radiometric BACTEC™ system is used to test the sensitivity of all primary antituberculous drugs (i.e., isoniazid, rifampin, pyrazinamide, and ethambutol).

Additional Evaluation

Isolation of Aspergillus or Nocardia from a patient without a known immunodeficiency should trigger a workup for an underlying host immune defect. Such a workup should include, at a minimum, evaluation of B cell–mediated humoral immunity (serum Igs and isohemagglutinins) and T cell–mediated cellular immunity (complete blood count [CBC] and differential, absolute lymphocyte count, peripheral smear, platelet count, and erythrocyte sedimentation rate [ESR]). The most common cause of immunodeficiency currently is acquired immunodeficiency syndrome (AIDS). AIDS and iatrogenic deficiencies that result from therapies that modulate the immune system (e.g., corticosteroids, posttransplant immunosuppression, and cytotoxic chemotherapy for malignancies) are leading causes of chronic infections. Primary (congenital) immunodeficiency syndrome associated with a hand infection is rare but has been reported.

An algorithm for requesting stains and cultures of biopsy material is useful in the operating room. When tenosynovitis, synovitis, or osteomyelitis is encountered during biopsy, the responsible organism is generally not discernible because the infected tissue does not have pathognomonic characteristics. Certain types of tenosynovitis have a high tendency of recurrence unless radical surgical excision is combined with appropriate antibiotics such as in the following infections: actinomycosis, sporotrichosis, coccidioidomycosis, M. terrae, and M. avium. Thus complete synovectomy is reasonable at the time of biopsy or surgery because this will reduce the microbial burden for subsequent antibiotic treatment. This is a reasonable argument for intraoperative smear staining and frozen section.

An exception to this approach is when the diagnosis of TB is endemic in a country (e.g., India, Hong Kong) or when diagnosis is known, such as in a patient with positive stains from pus, exudate, synovial fluid, sputum, or gastric washings for mycobacteria. The excised synovium should be sent for special stains and cultures at three temperatures: M. marinum, M. chelonae, M. hemophilum, and S. schenckii grow best at 30°C; M. xenopi at 42°C; and the rest at 37°C. M. avium, M. fortuitum, M. terrae, and M. chelonae require prolonged incubation, and some require special media— M. hemophilum grows only in a hemoglobin-reinforced medium, M. malmoense requires a pyruvate-containing medium. Pus from septic tenosynovitis may yield profuse growth of A. actinomycetemcomitans if grown in the presence of CO ₂ . Otherwise, it is difficult to grow and identify the organism. Actinomyces spp. and Nocardia spp. grow only in anaerobic media.

Etiology and Epidemiology

Although two serotypes of HIV are currently recognized, namely HIV-1 and HIV-2, the term HIV is generally used to designate HIV-1, which is the major virus. Less than 100 cases of HIV-2 infections are reported in the United States. AIDS syndrome is defined by the development of serious opportunistic infections, neoplasms, or other life-threatening manifestations that result from progressive HIV-induced immunosuppression. HIV was identified to infect lymphocytes by Barre-Sinoussi and her mentor Montagnier of France in 1983 for which they were awarded Nobel prize in 2008. AIDS has affected approximately 60 million people globally.

Globally, 78 million people have become infected with HIV and 35 million have died from AIDS-related illnesses since the first cases of HIV were reported more than 35 years ago. There were approximately 40 million people worldwide living with HIV/AIDS in 2017. Of these, approximately, 1.8 million were children (<15 years old). Most of these children were infected by HIV-positive mothers during pregnancy, childbirth, and breastfeeding. An estimated 1.8 million individuals worldwide became newly infected with HIV in 2017—about 5000 new infections per day. This includes 180,000 children (<15 years). Most of these children live in sub-Saharan Africa and were infected by their HIV-positive mothers during pregnancy, childbirth, or breastfeeding. In 2017, 21.7 million people living with HIV (59%) were accessing antiretroviral therapy (ART) globally, an increase of 2.3 million since 2016. People living with HIV who adhere to HIV treatment and maintain an undetectable viral load have effectively no risk of sexually transmitting HIV to their HIV-negative partners.

AIDS-related deaths have been reduced by more than 51% since the peak in 2004. In 2017, 940,000 people died from AIDS-related illnesses worldwide, compared with 1.9 million in 2004. Effective treatment with antiretroviral drugs has controlled the virus so that people with HIV enjoy healthy lives and reduce the risk of transmitting the virus to others. The risk of acquiring HIV is 27 times higher among men who have sex with men, 23 times higher among people who inject drugs, 13 times higher for female sex workers, and 13 times higher for transgender women.

TB remains the leading cause of death among people living with HIV, accounting for around one in three AIDS-related deaths. In 2016, 10.4 million people developed TB disease, and 1.2 million were living with HIV. People living with HIV with no TB symptoms need TB preventative therapy, which lessens the risk of developing TB and reduces TB/HIV death rates by around 40%. It is estimated that 49% of people living with HIV and TB are unaware of their coinfection and are therefore not receiving care. Detailed statistics on AIDS are available from the CDC’s HIV Surveillance Supplemental Report.

In the United States in 2016, approximately 1.1 million people were living with HIV. About 15% of them were unaware of their infection. An estimated 38,700 Americans became newly infected (incidence) with HIV in 2016. Men who are gay, bisexual, and who have sex with men bear the greatest burden by risk group, representing an estimated 26,000 of new HIV infections per year. The highest percentages of HIV infections were attributed to male-to-male sexual contact (68.2% overall and 83.5% among males); among females, the highest percentage of HIV infections was attributed to heterosexual contact (88.6%). In 2016 the rate was highest for persons aged 25 to 34, followed by persons aged 35 to 44 years; the highest rate was for black/African Americans; the rate for males (23.9) was 4.7 times the rate for females.

For information on the classification and clinical diagnosis of AIDS, see the online version of this chapter at Elsevier eBooks for Practicing Clinicians ( ExpertConsult.com ).

Classification and Clinical Diagnosis

The current CDC classification for HIV infection is based on clinical conditions associated with HIV infection ( eTable 3.1 ) and CD4 ⁺ T lymphocyte counts ( eTable 3.2 ). Thus there are three clinical grades based on three ranges of CD4 ⁺ cell counts (see eTable 3.2 ). This combination grades HIV infection into nine mutually exclusive categories as shown in the table. Current clinical staging approaches favor use of CD4 ⁺ lymphocyte counts and plasma viral load assays. FLOAT NOT FOUND FLOAT NOT FOUND

After initial infection, the HIV enters various types of cells in the body, including CD4 ⁺ lymphocytes, dendritic cells, mononuclear phagocytes, and others. Once in intracellular locations, the virus is safe from antibody neutralization. The symptoms of AIDS do not usually occur until the blood count of CD4 ⁺ T cells is below 200/mm ³ . The patients in all categories whose CD4 cell count is <200/mm ³ are now considered as having AIDS. Most patients with truly opportunistic infections have CD4 counts <100/mm ³ . Those with CD4 counts <50/mm ³ are at high risk of death from serious life-threatening opportunistic infections.

There are three clinical categories of HIV infection relevant to hands and upper extremities.

• Category A—Asymptomatic HIV infection, persistent generalized lymphadenopathy, acute (primary) HIV infection with accompanying flu-like syndrome (acute retroviral syndrome).

• Category B—Bacillary angiomatosis, herpes zoster with at least two episodes or in more than one dermatome.

• Category C—The deficiencies in T cell–mediated immunity in patients with AIDS leads to impaired immunity to viruses, fungi, and protozoa, which otherwise are easily controlled by a normal immune system.

Many of the malignancies that are frequent in patients with AIDS are associated with oncogenic viruses. Kaposi sarcoma is associated with the human herpes virus 8 infection. Many of the lymphomas that occur in patients with AIDS are associated with the Epstein-Barr virus. Lots of the skin and cervical carcinomas that occur in patients are associated with the human papillomavirus. Bacterial infections, multiple or recurrent, coccidioidomycosis, cryptococcosis, herpes simplex virus infection for longer than 1 month, histoplasmosis, Kaposi sarcoma, Mycobacterium tuberculosis, nontuberculous mycobacteria, and wasting syndrome of HIV infection are indicator conditions of infections relevant to hand surgery.

Clinical Manifestations of AIDS Infection in the Hands

Blue nails and clubbing are both a sign of HIV infection. ^, Red fingers syndrome has been reported in patients with HIV and hepatitis C infection. Bacterial, tubercular, fungal, protothecal, leishmanial, and herpes virus (herpes simplex and herpes virus type 8) infections and malignancies have occurred in the hand.

Glickel, Ching and coworkers, Gonzalez and coworkers, McAuliffe et al., and Seltzer and associates described hand infections in patients with HIV disease in the late 1990s. Approximately 10% of the patients who presented with hand infections in metropolitan hospital emergency departments had HIV infection. Of the intravenous drug users who presented with hand and upper extremity infections, 80% had HIV infection. Glickel suggests that diagnosis of AIDS should be considered when there is an unusual hand infection. It should be taken into consideration for any patient who needs a repeat drainage or debridement procedure. Fingers of those with AIDS may be red with painless erythema and periungual telangiectasia. Nails may be blue or show clubbing. Ching and colleagues noted that among 14 AIDS patients with hand infections, almost one-third needed multiple debridements and resulted in amputation of a finger or hand.

McAuliffe et al., in a review of 74 HIV-seropositive patients who were treated for upper extremity infections, found that intravenous drug use was the most common risk factor for HIV infection as well as the most common cause of the infection necessitating admission. These 74 patients were admitted a total of 97 times for treatment of 89 different infections and underwent 120 surgical procedures. Twenty-six infections (29%) required more than one operation, and 11 (12%) resulted in amputation. Patients with AIDS were significantly more likely to present with spontaneous infection than were those who were HIV seropositive. The infections may be seen early in the course of the disease, and in one-half of the patients, they preceded the diagnosis of AIDS. Gonzalez et al., in a study of 28 patients, found 5 who had necrotizing fasciitis; all needed more than one debridement, and one required forequarter amputation. Since 2000, AIDS was controlled with multiple drug regimen and hand infections have now dropped to case reports.

TB remains the main infection in patients with AIDS. HIV-infected subjects should be screened for TB and TB cases should be tested for HIV. A case of a rifampicin-resistant M. marinum organism in an immunocompromised HIV-1 individual was reported recently. A case of TB dactylitis occurred in a patient with AIDS who originated from the African Ivory Coast. A case of Mycobacterium szulgai infection in an AIDS patient resulted in osteomyelitis of the hand (and toe) accompanied by multiple cutaneous ulcers of the forearm (and of the chest). Hansen disease and HIV infection may coexist. Human papillomavirus infection in AIDS can cause severe hand infections. A chronic, unrelenting herpetic whitlow may be the first manifestation of HIV infection. Severe, progressive herpetic whitlow may occur in an acyclovir-resistant patient with AIDS. Human papillomavirus infection causing multiple invasive squamous cell carcinomas of the fingernails occurred in an AIDS patient with bone invasion that required amputation of distal phalanges of several fingers. A 32-year-old HIV-infected man presented with a syphilitic ulcerating skin lesion on the upper arm. Herpes ulcer of a finger may be misdiagnosed as pyoderma gangrenosum. Leishmania species infection in a patient with AIDS may cause digital necrosis. Two corticosteroid-treated patients with cutaneous cryptococcal infection of the hand included one patient with pustulous lesions on the back of his left hand and cellulitis of his left forearm, the other patient who had ulcerous lesions of the right forearm (and cellulitis of the right lower leg). In both cases diagnosis was suggested by histopathological examination of a biopsy and confirmed by culture. Woolrich described cutaneous protothecosis of hand in an AIDS patient. Townsend et al. reported a case of Candida tenosynovitis in an AIDS patient. AIDS may infect vasa vasorum of an artery and cause an aneurysm, and brachial artery aneurysm in a patient with HIV infection was reported.

Bacillary angiomatosis

Bacillary angiomatosis was first described in 1983 in AIDS patients and is an infectious, cutaneous, vascular, tumor-like disorder found almost exclusively in HIV-positive individuals. Three species of Bartonella are responsible for the vast majority of infections in humans: B. henselae, B. quintana, and B. bacilliformis and is transmitted by cats, ticks, fleas, and lice. The lesion may be a pea-sized nodule with or without plaques when first noticed ( Fig. 3.1 ). It may be nonpedunculated or pedunculated, and the lesions can occur anywhere on the body and have solitary (see Fig. 3.1 ) or multiple nodules. When punctured by a needle or scalpel, the lesion may bleed profusely. It may resemble a benign pyogenic granuloma or present as an ulcer ( Fig. 3.2 ). It has been reported in an HIV-positive child. A fine needle aspiration was able to diagnose a case of intramuscular bacillary angiomatosis of deltoid.

Histologically, it is characterized by vascular perforation, hemorrhage, and necrosis of skin. The diagnosis of bacillary angiomatosis is best made by fine-needle aspiration biopsy. Warthin-Starry stains show perivascular accumulations of bacilli; these findings may be confirmed by electron microscopy, although this is not usually necessary. The diagnosis can also be established by culture of the organism in several special media or by detection of Bartonella DNA by PCR. Serologic assays for anti- Bartonella antibodies are available through the special pathogens branch of the CDC.

If left untreated, bacillary angiomatosis follows a progressive and potentially fatal course. Once it is properly identified, treatment consists of prolonged therapy with erythromycin or doxycycline, which prevents recurrence of bacillary angiomatosis. Fluoroquinolones, other macrolides, and trimethoprim-sulfamethoxazole also have activity against Bartonella.

Treatment of AIDS

Currently most patients on their initial antiretroviral regimen take a combination of two nucleoside reverse transcriptase inhibitors with either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor. Before the availability of these drugs, the median survival after the diagnosis of AIDS was 12 to 18 months. Now antiretroviral treatment leads to a near-normal life expectancy.

Classification

Two types of cutaneous warts are widespread in hands. Common verrucated warts, Verruca vulgaris ( L. verruca, “a little hill”), represent 95% of cutaneous hand warts. The second most common warts are flat or plane (verruca plana) (5%). Both types are seen predominantly in children but also affect adolescents and young adults. Adults at high risk for the development of warts are veterinary surgeons, butchers, meat packers, fowl handlers, poultry processors, and fish handlers—all occupations in which hands are frequently exposed to moisture. It may occur as a cross infection from one finger to another from multiple reuses of an unsterilized lancet for monitoring blood sugar in diabetic patient. In immunocompromised subjects, warts are more pervasive, and more resistant to treatment, for example in renal failure patients.

Pathogenesis of Human Papillomavirus

The incubation period of HPV disease is 1 to 3 months. The virus infects only the epidermis. Warts have a characteristic histologic appearance, showing acanthosis, papillomatosis, hyperkeratosis, and parakeratosis.

Diagnosis

Common verrucated wart

The clinical appearance of a common verrucated wart is quite characteristic and usually consists of a single lesion on the hand, fingers, or around the nail. It is a cauliflower-like, raised, demarcated, and grayish mass, with an irregular surface traversed by many projections ( Fig. 3.3A ). It is often painless, and the adjacent skin is healthy. Warts in the palm may be painful because of pressure during grip. If untreated, the common wart can multiply and infect the surrounding skin or the opposite hand. When multiple, there may be several dozen “seed lesions” surrounding a larger and older “mother wart.” A cluster of closely spaced warts can coalesce into a large “mosaic wart.” “Kissing warts” are seen in areas of skin contact (web spaces) and may represent direct inoculation. Filiform warts are slender, finger-like papules. Periungual warts can extend into the nail bed under the nail plate (subungual warts) and can persist for many years in spite of conservative treatment.

Treatment

No antiviral chemotherapy is available for HPV warts. They are a cosmetic nuisance in most cases and often disappear spontaneously; this seems to occur in 50% of children within a year and 90% within 5 years. Fluctuations in immunity to HPV may be responsible for spontaneous regression or resurgence of preexisting warts. If left untreated, however, some may persist for many years and become larger. A periungual wart can lead to bone destruction of distal phalanx. Rarely does a wart transform into a carcinoma.

Conservative treatment remains the hallmark for management of common warts. When they do not respond to conservative treatment or are too large and cosmetically unacceptable, surgical excision is a good option that cures the problem. Multiplicity of treatments for warts attests to the lack of any single satisfactory therapy method. Cooperation and preference of the patient or parent and experience of the physician determine the appropriate treatment modality.

Most therapeutic modalities consist of chemical or physical destruction of warts. Surgical excision of large, isolated lesions can be successful. In contrast, warts in immunosuppressed adults are likely to be progressive, recalcitrant, recurrent, and unresponsive to all but the most aggressive therapy and are more likely to become malignant. Infectious disease and dermatology specialists should be consulted for treatment recommendations. Patients with verrucated warts usually seek treatment for cosmetic reasons. Patients with flat warts usually do not seek treatment.

Human Orf (Farmyard Pox, Milker’s Nodule, Ecthyma Contagiosum, Contagious Pustular Dermatitis)

Human orf infection is important to a hand surgeon because it causes a large tumor-like lesion in immunodeficient hosts that resolves with simple topical cidofovir application. Misdiagnosis has led to unnecessary excisions, multiple excisions, and even amputation. Four cases of human orf were reported in the United States between 2009 and 2011 from household exposure to lamb and goat slaughter.

The word “orf” is an old Anglo-Saxon name for cattle, and the disease is endemic in sheep and goats. Orf is caused by a large paravaccinia DNA virus that belongs in the subgroup of pox viruses. It is common in humans who have direct contact with infected sheep and goats or with products or objects that come in contact with sheep and goats. The virus can persist for long periods on such objects as fences, barn doors, and feeding troughs from which the disease is indirectly transmitted to a susceptible host. In 1 year, 1.4% of 16,484 sheep and goat handlers in New Zealand were infected. The risk was highest (4%) with mutton slaughterers. It occurs on the exposed parts of the body, especially the hands. Human orf is an occupational disease in “risk populations” such as shepherds, sheep shearers, butchers, and veterinary surgeons.

There is a yearly outbreak of orf infection of the hand in Saudi Arabia. Two million people visit there for “Hajj” every year, and hundreds of thousands of sheep are slaughtered by nongloved hands at the end of the ceremony. Inoculation occurs in preexisting or incidental new injuries of the hand from the infected animals. Outbreaks in Turkey and Belgium occur 2 to 3 weeks after the Islamic “Feast of Sacrifice” (Aid el-Kebir or Eid el-Adha) in men who bleed the sheep and in women who handle their skin and meat. The epidemic is predictable 9 weeks after the end of Ramadan every year, and 75% of patients are Islamic.

Clinical Findings

Ninety-five percent of the lesions are on the finger ( Fig. 3.4 ), hand, wrist, or forearm—the area of contact with infected animals. The lesion is usually unilateral, and it is rarely bilateral. The lesions may be single (see Fig. 3.4A ) or multiple (see Fig. 3.4B ). It may occur as paronychia and is distinguished from bacterial paronychia by the presence of a nodule with central red discoloration, a middle bluish-white ring, and peripheral erythematous or violaceous halo (see Fig. 3.4A ). There is a history of exposure to sheep or goats, a goat/sheep bite, or handling of goat/sheep for “sacrifice.” After an incubation period of 3 to 7 days, the infected skin lesion erupts clinically. In humans, orf is commonly known as ecthyma contagiosum or contagious purulent dermatitis (CPD), but this is in part a misnomer because pustules are not purulent (ecthyma = purulent pustules) in human orf.

Leavell described the lesion in six clinical stages in a study of 19 cases of human orf. Each stage lasts approximately a week, and the disease resolves without treatment in approximately 6 weeks (range, 14 to 72 days). The first stage is characterized by an erythematous macule or papule. In the second (target stage) the lesion turns into a nodule. The lesion may be bullous at this stage (see Fig. 3.4B ). The third, or the weeping, stage is characterized by a weeping surface on a nodule. The fourth stage consists of a thin yellow crust with underlying black dots over the nodule. The fifth (papillomatous stage) consists of small surface papillomas and finger-like projections of the epidermis. The sixth and final stage is characterized by reduction in the size of the lesion and formation of a thick crust that looks like an ulcer before final healing. Lesions do not always correspond to these stages and may present as an erythematous nodule, a tense bullous lesion, a giant lesion, or a felon. In a felon there is an absence of local pain and drops of clear fluid may exude from the lesion.

Milker’s Nodule (Paravaccinia Virus, Pseudocowpox)

Paravaccinia virus that infects sheep and goats also infects cows. In humans, nodules on the hand caused by this virus are called milker’s nodules because milkers acquire hand infections from the cow’s infected udder through direct contact or indirectly through contaminated objects. Milker’s nodule is usually regarded as an occupational disease of dairy farm workers.

The initial lesion is on the exposed part of the hand and upper extremity in more than 50% of cases. The incidence of milker’s nodule has fallen since the majority of cows are now milked by machine. It has been reported in a healthy young cattle veterinarian. The bovine virus is morphologically indistinguishable from the ovine orf virus. When the animal source is unknown, it is not possible to clinically differentiate between ovine (sheep and goat) and bovine (cow) nodular lesions on the exposed hand and upper extremity and under the electron microscope. Diagnosis of the disease is based for the most part on knowledge of the animal source. Rarely, the lesion of pseudocowpox presents as a black necrotic ulcer clinically indistinguishable from anthrax. Large eosinophilic intracytoplasmic inclusions within epidermal cells and DNA sequencing to match paravaccinia can quickly distinguish the two when anthrax has to be ruled out promptly.

Hand, Foot, and Mouth Disease

Coxsackievirus 16 (CA16), coxsackievirus A16 and A6 (CA16 and CA6), and human enterovirus 71 (EV71) are the main pathogens causing HFMD. CA16 was first isolated in Albany, New York, in 1948. Both are a member of human enterovirus A species. CA16 is a small, nonenveloped particle that contains a single-stranded viral RNA. In infants and young children, CA16 is a major pathogen associated with HFMD. In recent years, CA16 and EV71 have often circulated alternatively or together in the Western Pacific region epidemics and has become an important public health problem in China and surrounding regions. HFMD caused by CA16 infection is generally thought to be mild and self-limiting. However, recently several severe and fatal cases involving CA16 have been reported. Studies have shown that co-infection with CA16 and EV71 can cause serious complications in the CNS and increase the chance of genetic recombination, which may be responsible for the large HFMD outbreak in mainland China in 2008. Epidemics have been reported in England and Wales, Taiwan, Singapore, Vietnam, India, and mainland China caused by CA16 or EV71 or by both. Compared with the Western Pacific region, where HFMD outbreaks were associated with severe symptoms and death, there were fewer reported HFMD epidemics and severe cases in Europe and Americas.

Clinical Findings

A. actinomycetemcomitans may cause chronic tenosynovitis of dorsal wrist tendons or finger flexor tendons. A deep hand laceration from a tooth may cause recurrent abscesses and a draining sinus at the site of original trauma in an adult patient. X-rays may show chronic osteitis of the injured metacarpal head.

Diagnosis

Pus from a draining sinus may yield profuse growth of A. actinomycetemcomitans if grown in the presence of CO ₂ . Otherwise, it is difficult to grow and identify the organism. Differential diagnosis should include actinomycosis from Actinomyces israelii and aerobic cultures in properly sealed containers should be included for microbiology laboratory.

Treatment

Incision, drainage, and ampicillin may completely eliminate the infection. Tenosynovectomy and intravenous gentamicin or oral tetracycline may also resolve the infection without further recurrence.

Etiology and Epidemiology

Actinomycosis is most commonly caused by Actinomyces israelii, a normal inhabitant of the oral cavity. Actinomycosis, by definition, is caused by endogenous human flora, whereas actinomycetoma, described later, is caused by exogenous pathogenic bacteria in soil. Two percent of actinomycosis cases occur in the upper extremity. Most cases of hand actinomycosis have been noted sporadically in case reports.

Clinical Findings

In the hand, a closed-fist injury or a bite is the most common cause of actinomycosis. Oral flora may be implanted over the metacarpophalangeal joint or the metacarpal head on impact. This type of injury is designated as “punch actinomycosis.” A dentist can contract it during examination of the mouth without gloves.

Clinical presentations are varied. In the early stages it may appear as nonspecific, painful induration, or as a nontender, mobile nodule. The nodule may later form a draining sinus. Any suppurative inflammatory reaction that stubbornly resists treatment and tends to discharge continuously should lead one to suspect the possibility of actinomycosis, especially if it is at the site of a human bite wound. It may start as an acute abscess, or there may be a painless and persistent swelling of the hand after the acute inflammation from the initial trauma subsides. Subcutaneous tissue may become indurated and adherent to subjacent bone. It may present as a recurrent swelling with sinuses that intermittently discharge purulent fluid. When tendon sheaths are involved, purulent material may contain melon seeds, as in TB and fungus infections. A recurrent fluctuating palmar abscess may occur. A primary cutaneous actinomycosis of upper extremity may masquerade as soft tissue neoplasm.

Once actinomycosis is established locally, it spreads contiguously in a slow but progressive manner, ignoring tissue planes. In the forearm, it may arise as a mass from hematogenous spread and can masquerade as a soft tissue neoplasm. Finally, contiguous invasion of subjacent bones occurs. The bones of the hand and wrist may have cystic, sclerotic, or lytic changes. Isolated actinomycosis osteomyelitis is rare and may occur in the proximal phalanx or metacarpal. Infectious destruction may even cross from the dorsal-to-palmar or palmar-to-dorsal side of the hand. Infection of the upper arm can occur but is rare. Axillary nodes may become enlarged.

Diagnosis

The identification of “yellow sulfur granules” of actinomycosis organisms from a draining sinus or pus from an abscess is diagnostic. Sulfur granules are a yellow conglomeration of microorganisms that form only in vivo and characteristically are identified in bandages that cover a draining sinus. Biopsy is necessary to obtain clinical material for diagnosis if a draining sinus is not present. A specimen must be sent and cultured in anaerobic media. Cultures are positive in only 25% of the cases, perhaps because the specimen was not sent to the laboratory in anaerobic media. Histopathology of infected tissue shows the characteristic organisms and diagnosis can be firmly made in the absence of positive cultures. Cultures should include A. actinomycetemcomitans grown in presence of carbon dioxide.

Treatment

Penicillin is the treatment of choice. Intravenous penicillin must be employed in high doses for several weeks followed by oral penicillin or amoxicillin for 6 to 12 months. In the short term, treatment with antibiotics may result in temporary cessation of drainage. When the therapy is discontinued, however, drainage may recur. Without definitive treatment, the infection can persist for several decades and cause extensive deformities. For penicillin-allergic patients, tetracycline, erythromycin, minocycline, and clindamycin are alternatives. If infection recurs, surgical debridement is an essential component of further antibiotic treatment.

Etiology and Epidemiology

In the United States the annual incidence of anthrax exposure declined from 130 cases in the early to mid-1900s to a single case reported in 1992. It reappeared in the United States as a bioterrorism method in 2001. Ten cases of cutaneous anthrax and 10 cases of pulmonary anthrax (four fatal) were reported within a month after September 11, 2001. Of the numerous biologic agents that may be used as weapons, anthrax is one of the most devastating. It is still commonly reported from Iran, Hungary, and Turkey.

Anthrax infection is caused by Bacillus anthracis, a gram-positive, encapsulated, spore-forming bacillus. The name anthrax (Greek anthracis, “coal”) refers to the typical black eschar that is seen on affected areas. Ninety-five percent of patients with cutaneous anthrax are diagnosed when they have a relatively painless necrotic black ulcer. Humans can acquire the disease directly from contact with infected herbivores (i.e., agricultural anthrax); indirectly from contaminated meat, wool, hides, or leather from infected animals (i.e., industrial anthrax), through accidental inoculation in the laboratory (i.e., laboratory-acquired anthrax); or unexpectedly from exposure to “weaponized” spores of bioterrorism (i.e., biocriminal anthrax). The clinical forms include (1) cutaneous anthrax, which accounts for more than 95% of cases; (2) intestinal anthrax, from eating infected meat; and (3) pulmonary anthrax, from inhaling spore-laden dust. Cutaneous anthrax of the hand and upper extremity occurs in approximately one-third of all cases in an epidemic and may be presented to a hand surgeon primarily.

Clinical Findings

Cutaneous anthrax occurs after the deposition of the organism into the skin at the site of a previous cut or abrasion. The lesion may occur on a finger or hand. After an incubation period of 3 days (range, 1 to 12 days), the skin infection begins as an area of local edema that becomes a pruritic macule or papule. The papule progresses to a vesicle or vesicles, surrounded by erythema, in 1 to 2 days. The vesicle contains clear or bluish fluid ( Fig. 3.5 ). Patients may have a fever and regional lymphadenopathy. The vesicles rupture in 2 to 14 days and leave behind a painless black skin ulcer that becomes a black eschar ( Fig. 3.6 ). The eschar contracts into an ulcer, usually 1 to 3 cm in diameter, with small, 1- to 3-mm vesicles surrounding the ulcer. A characteristic black necrotic center develops by 4 weeks, often associated with extensive local edema. Unless the disease becomes systemic, the eschar may dry, loosen, and fall off in the next 1 to 2 weeks. A lesion on the finger may heal with full mobility. In some cases, the skin may necrose and need skin graft or flap. The common clinical description “malignant pustule” is actually a misnomer because the cutaneous lesion is not purulent.

Diagnosis

Anthrax exposure is diagnosed by isolating B. anthracis from the vesicular fluid of skin lesions. Gram-staining reveals bacilli in the subcutaneous tissue.

Treatment

About 20% of untreated cases of cutaneous anthrax become systemic and result in death. Antibiotic therapy does not appear to change the course of eschar formation and healing; however, it does decrease the likelihood of systemic disease and death. When treated with appropriate antibiotics, the death rate is <1% and lesions resolve without complications or scarring in 80% to 90% of cases. It is rare for the black eschar on the finger, hand, and forearm to extend deeper than the dermis. If it does extend deeper, soft tissue coverage may be required. ^, The eschar may extend down to the muscle fascia. In these cases, the eschar is excised, and the defect is grafted using a skin flap. A patient may develop anthrax of the finger after an accidental injection with Bacillus anthracis . A split-thickness skin grafting may be needed for the finger skin coverage.

Duration of antibiotic treatment for animal-acquired and bioterrorism-acquired anthrax differs. Animal-acquired anthrax is treated with doxycycline (100 mg PO bid), ciprofloxacin (500 mg bid or 750 mg Od), or amoxicillin (500 mg tid) orally for 7 to 10 days. Lesions become sterile within 24 hours and resolve within weeks. Direct person-to-person spread of anthrax is extremely unlikely. There is no need therefore to treat contacts of infected individuals unless they were also exposed to the same primary source of infection. Bioterrorism-acquired anthrax is classified either as anthrax exposure or anthrax infection. Both exposure and infection are treated for 60 days because aerosol inhalation of anthrax is presumed in instances of bioterrorism.

The case fatality rate of 11 treated cases of an inhalational bioterrorism event in 2001 was 45%. A bioterrorism event should be reported to the CDC website at https://emergency.cdc.gov/bioterrorism/ , a website that also provides information about clinical diagnosis and management of anthrax and all agents of bioterrorism. In the United States anthrax vaccine is recommended only for high-risk populations, including military combat personnel, persons who work directly with the organism in a laboratory, those who work with imported animal hides or furs, or those who handle potentially infected animal products in high-incidence areas.

Etiology and Epidemiology

Botryomycosis is a rare, chronic, granulomatous, suppurative, bacterial skin and subjacent soft tissue infection that produces loose clumps of bacteria that resemble grains. Among more than 100 cases of botryomycosis reported in the literature, three cases affecting the hand have been identified. The characteristic histologic finding of “granules” in clusters is the origin for the term botryomycosis (Greek botrys, “bunch of grapes” in histology; mycosis for its clinical and histologic resemblance to fungal infection). The condition is in fact produced by bacteria and is truly a “granular bacteriosis.” Staphylococcus aureus, Pseudomonas vesicularis, Moraxella nonliquefasciens, and TB have been reported to cause botryomycosis of the hand. The first case of tuberculous botryomycosis was reported in 2014 and was cured by antituberculous chemotherapy. A case of staphylococcal botryomycosis in a patient with AIDS was successfully treated with Augmentin.

Diagnosis

Clinically, histologically, and therapeutically this bacterial infection resembles a fungal one.

Treatment

The condition may respond rapidly to oral antibiotics, or it may be resistant to antibiotic therapy and need complete excision and skin grafting to eradicate the infection.

Etiology and Epidemiology

Brucellosis is named after Sir David Bruce (1855–1931), the Scottish physician who identified the bacterium. Brucellae are gram-negative coccobacilli that chronically infect animals. Virtually all human infections derive from direct or indirect contact with cattle (B. abortus) or goats and sheep (B. melitensis) . Routes of transmission to humans include cuts in the skin, inhalation of infected aerosols, and ingestion of unpasteurized milk. Brucellosis is endemic in the Middle East, South America, and the Mediterranean area. In Texas and California, the epidemiology of brucellosis has changed from a disease associated with exposure to cattle to one linked to ingestion of unpasteurized goat’s milk products imported from Mexico.

Clinical Findings

The musculoskeletal system was affected in approximately one-third of 169 cases. Osteomyelitis and septic arthritis involved the upper extremity. Septic arthritis occurred in the sternoclavicular joint in three cases (1.8%), shoulders in eight (5%), elbows in nine (5.3%), and wrists in six (3.5%). Osteomyelitis occurred in four (2.4%) and tendinitis was noted in one (1.2%). Dactylitis may occur with or without osteoarticular brucellosis. One case of a primary brucellar tenosynovitis has been reported with rice bodies. Rice bodies are tenosynovial fibrin bodies that detach from the parent tenosynovium and grow, and they may be found in brucellosis but also in TB, NTM infections, and fungal infections (e.g., blastomycosis, coccidioidomycosis, histoplasmosis, and sporotrichosis) as well as in rheumatoid arthritis.

Diagnosis

Diagnosis is made when blood culture or bone needle aspiration culture grow B. melitensis. In chronic brucellar olecranon bursitis, synovial fluid and serum are positive for serologic tests and B. melitensis grows on chocolate agar.

Treatment

Repeated 4- to 6-week courses of rifampin and tetracycline may cure the patient without a relapse.

Etiology and Epidemiology

Mycetoma is a twofold disease, caused either by large filamentous bacteria (actinomycetoma) or by fungi (eumycetoma) (synonyms: maduromycosis, Madura foot). Eumycetoma is so named because it is caused by the eumycetes group of fungi. Predictably, fungal eumycetoma is more invasive and more difficult to treat than bacterial actinomycetoma. (Actinomycosis caused by Actinomyces israelii is a different disease and was described previously.) Mycetoma is characterized by a slowly evolving, often painless, cutaneous and subcutaneous destructive inflammatory granuloma riddled with abscesses; multiple sinuses with interconnecting channels; and fistulas that drain characteristic colonies of the infecting organisms in the form of grains and granules.

The grains are dense clusters of organisms and are the defining characteristic of this infection. The granules, the colonies of the organisms, occur in a triad of chronic infections: mycetoma (eumycetoma and actinomycetoma), actinomycosis, and botryomycosis. Only 2% to 12% of all mycetomas involve the hands, whereas the majority (70%) occur in the feet. Twenty-one cases of the hand and arm were reviewed by Moore in 1954. Since then the Mycetoma Research Centre, University of Khartoum, Khartoum, Sudan, reviewed 533 patients with hand mycetoma seen between 1991 and 2015, comprising 7% of total patients seen during this period. In this review, 67% of the patients had mycetoma of less than 5 years duration at presentation. In only 64% of cases was the disease diagnosed early at a nodular or abscess stage. Approximately 46% of patients had small lesions less than 5 cm in diameter, 26% had moderate lesions between 5 and 10 cm in diameter, and 23% had massive lesions larger than 10 cm in diameter. About 80% had active or closed sinuses and 40% had discharge with grains.

A mycetoma caused by aerobic bacteria, Actinomyces spp., is referred to as actinomycetoma. Actinomyces spp. are “higher” bacteria with morphologic characteristics between bacteria and fungi. The majority of actinomycetomas in North America are caused by Pseudallescheria boydii (its asexual anamorph is Scedosporium apiospermum; previous names, Allescheria and Monosporium ). Nocardia is another cause of mycetoma in the hand. It is important not to misdiagnose it as actinomycosis on gross and microscopic examination because there is presence of granules in both. A mycetoma caused by true fungi is referred to as eumycetoma, true mycetoma, maduromycosis, or Madura foot—named after the city of Madura from South India where the first cases were described. More than 30 fungi are known to cause eumycetoma. Distinguishing mycetoma caused by the Actinomyces spp. bacteria (actinomycetoma) and fungi (eumycetoma) is extremely important. Actinomycetoma and eumycetoma both clinically look the same but the treatment and prognosis for the two are distinctly different. In contemporary medical mycology, actinomycosis is not classified as an actinomycetoma because the etiologic agents of actinomycosis are anaerobic and endogenous in the oral flora. Conventionally, only infections caused by exogenous aerobic pathogenic bacteria and fungi are called actinomycetoma and eumycetoma. This clearly differentiates actinomycosis from actinomycetoma.

The disease is endemic in tropical, subtropical, and temperate regions, predominating between latitudes 30°N and 15°S. Most cases occur in Africa, especially Sudan, Mauritania, and Senegal; India; Yemen; and Pakistan. In the Americas, the countries with the most reported cases are Mexico and Venezuela. Actinomycetoma is more common in Latin America, with Mexico having the highest incidence. At last count, there were 2631 cases reported in Mexico. Eumycetoma is rare in Mexico, constituting only 2% of cases. Worldwide, men are affected more commonly (70%) than women, which is thought to be related to a higher occupational risk during agricultural labor.

In the largest series of 533 mycetomas reported from Sudan, 80% were eumycetomas and 20% were actinomycetomas. Most patients (70%) were young adult males (18 to 30 years) of poor socioeconomic status and from rural areas of the Sudan, and 30% of the reported patients were children. Compared with patients with mycetoma in other parts of the body, they presented rather early, having noticed the lesion earlier because they frequently wash and examine their hands. No predisposing factors were evidenced in the study. The majority of patients (67.4%) had disease duration of less than 5 years at presentation. Pain was not a disease feature in this series and was present in only 23.1% of the patients. The right hand was affected most (60.4%), and 64% of them had a small lesion at presentation. Conventional x-ray was only helpful in patients with advanced disease with bone changes and the magnetic resonance imaging (MRI) accurately determined the soft tissue disease. Cytologic smears, surgical biopsies, histopathological examination, and grains culture were the principal diagnostic tools for identification of causative organisms. It was difficult to determine the treatment outcome due to the high rate of patient dropout during follow-up.

Microbiology

Mycetoma of the hand has been reported to occur from a wide variety of organisms; many of them are being reported for the first time. Major mycetoma bacteria and fungi are found all over the world and are associated with woody plants and soil. At times, granules are identified in the lesion but fail to grow organisms, and identification by a PCR is needed. In rare instances, the bacteriologic origin of mycetoma cannot be ascertained.

In the United States several cases of hand mycetoma have been reported, and they are equally divided between actinomycetoma and eumycetoma. Agents of mycetoma differ in various parts of the world. The most common cause of eumycetoma in the United States is Pseudallescheria boydii (asexual anamorph, Scedosporium apiospermum; previous names Allescheria, Monosporium, Petriellidium ) and of actinomycetoma is Nocardia. Madurella mycetomatis is the most common eumycetoma causative agent, while Streptomyces somaliensis and Nocardia spp. are the common actinomycetes causing actinomycetoma in the world. Madurella mycetomatis, Actinomadura madurae ( Fig. 3.7 ), and Nocardia brasiliensis are predominant in India. N. brasiliensis and A. madurae are the most common causes of actinomycetoma in Mexico and Central and South America. Actinomycetomas represent 98% of mycetomas in Mexico, and 86% of them are caused by Nocardia brasiliensis and 10% are caused by Actinomadura madurae. Streptomyces somaliensis, Actinomadura pelletieri, and Nocardia spp. are predominant in Africa. N. asteroides and Scecosporium apiospermum are reported to predominate in Japan.

Actinomycetoma of thumb was caused by Nocardia transvalensis. Actinomycetoma of the hand was caused by Nocardia asteroides and by a new and emerging actinomycetes, Gordona terrae. A case of hand eumycetoma caused by Arthrographis kalrae was reported in Japan and was successfully treated with itraconazole. A case of eumycetoma of the hand caused by Leptosphaeria tompkinsii, a black grain causative organism, was reported in the United Kingdom that did not respond to surgery and voriconazole. Phialophora jeanselmei (Torula jeanselmei) hand eumycetoma was reported in Thailand. A case of S. somaliensis hand actinomycetoma was reported in the United Kingdom and was sensitive to and treated with cotrimoxazole (trimethoprim/sulfamethoxazole, Bactrim) and streptomycin. A case of actinomycetoma of the hand caused by Gordona terrae was reported in the Netherlands and was cured in 2 weeks by only doxycycline. The first case of actinomycetoma of the hand caused by Nocardia caviae was reported in Brazil. Aspergillus nidulans may rarely cause eumycetoma of the upper extremity. Scedosporium boydii, Fusarium solani, and Acremonium recifei have also been reported to cause mycetoma of the hand.

Clinical Findings

A mycetoma is a characteristic clinical triad of tumification, draining sinuses, and granules in the discharging pus in the distal aspect of a limb. Swelling is woody and indurated (tumification), and multiple sinus tracts drain grain-filled pus; the grains are the infecting organisms. Old sinuses heal and new may grow. Characteristic grains in draining sinuses are 0.2 to 5.0 mm in diameter and may be black, white, yellow, pink, or red, depending on the causal organism. Grains may be difficult to locate in histopathologic sections and require multiple cuts through the paraffin-embedded tissue.

Mycetoma, regardless of fungal or bacterial origin, has a similar clinical presentation. The majority of the patients are males. Most patients in developed countries are between 30 and 60 years old. The male-to-female ratio is 5:1. It is rarer in children (30%). The disease begins following the traumatic implantation of the etiologic agent from the soil, thorn, or wood splinter into a bare hand of a healthy person. Total involvement of the hand and wrist together is far less than lower extremity. In children with mycetoma, 80% were eumycetoma. The lesions may be restricted to a finger, ^, palm, dorsum of the hand, dorsum of the wrist, forearm, or upper arm, shoulder, and neck. The lesion may be on both sides of the hand when the infection crosses the metacarpals from the dorsal-to-palmar or from the palmar-to-dorsal side of the hand.

Mycetoma infection begins in the skin and subcutaneous tissues as a nodule or nodules. Mycetoma tends to follow fascial planes as it spreads proximally and mediolaterally, and with increasing depth, it progressively infects and destroys all connective tissues and eventually bone (see Fig. 3.7 ). In the end, the untreated hand is deformed and functionless.

The annual incidence of nocardiosis in the United States has been estimated to be between 500 and 1000 cases, with 36% being cutaneous nocardiosis. The genus Nocardia comprises gram-positive, aerobic, acid-fast, and filamentous bacteria of which N. brasiliensis is usually associated with cutaneous and subcutaneous infection. The spectrum of nocardiosis of the hand manifests clinically as one of three types: (1) an acute infection consisting of cellulitis or abscesses; (2) lymphocutaneous infection with marching lymphangitis (sporotrichoid infection); (3) typical actinomycetoma stage I with nodules, stage II with purulent and or nonpurulent sinuses, stage III with spread to subjacent deep tissues, and stage IV with metastasis proximal to the limb.

Staging

Mycetoma of the hand and upper extremity has been graded into five stages. Initially, the lesion is a small, firm, painless subcutaneous nodule or nodules under the skin (duration, 2 to 3 months), which may grow to a large size (nodular, stage I). Nodules become abscesses and drain granules through sinuses to the surface of the skin or to the surface of an ulcerated nodule (duration, 4 to 12 months) (sinusoidal, stage II). Sinuses may close after pus and granules have been discharged. Old sinuses heal and new ones crop up. Radiographs show soft tissue swelling. If left untreated, the infection progresses to osteomyelitis (see Fig. 3.7C and D ; skeletal, stage III). Finally, limb deformity occurs over the course of a year or more (skeletal, stage IV). Lesions of the hand may metastasize to the axilla and the chest wall (metastatic, stage V). Radiographic signs include thinning of the metacarpals, bone erosions and cavities, sclerosis, and periosteal reaction (see Fig. 3.7A and D ). A network of connected sinuses is present in the soft tissues from the bone to the skin. Hand mycetoma has been reported to extend through the lymphatics to the chest wall and to the lung after many years (metastatic, stage V). Constitutional symptoms are absent unless there is superimposed bacterial infection. Pain is not a predominant symptom.

The patient, usually an immigrant, a rural farmer, or a laborer of lower socioeconomic status, postpones seeking medical care until the second or third stage is reached due to lack of pain in most cases (80%). Granules, which are aggregates of the organism, are discharged through the sinuses. Eventually, the hand and forearm become grossly enlarged, nodular, discolored, indurated, and deformed, although the patient may experience little pain or tenderness. The progression of the disease is marked by remissions and exacerbations. The period necessary for the development of the deformity varies from several months to several years. The extent of soft tissue invasion (staging) may be best evaluated with ultrasonography or MRI.

Diagnosis

Radiographs demonstrate extent of soft tissue swelling and bony involvement. MRI and ultrasonography better define the extent of soft tissue involvement. Dot-in-circle sign on MRI is characteristic sign for mycetoma. Hematoxylin and eosin stain of the grains is adequate in establishing the infecting organisms. Grain gram staining detects fine, branching hyphae in the bacteria of actinomycetoma. Gomori methenamine silver or periodic acid–Schiff stain detects the larger hyphae of fungus of eumycetoma. Species of the agent can often be recognized by the color, size, compaction, and hematoxylin-staining character of the grains when organisms fail to grow in cultures. Actinomyces spp. are recognized as 0.5 to 1 μm filaments and fungi by 2 to 5 μm wide hyphae. Culture should be held for at least 4 weeks. When grains are not available, fine-needle aspiration cytology (FNAC) or open biopsy for staining and culture and sensitivity is useful.

A more exact species diagnosis is made by microscopic observation and culture of a grain, which must be as free as possible from bacterial and other fungal contamination. A deep-tissue, wedge-shaped biopsy provides a good specimen for both histologic and microbiologic diagnosis and avoids the bacterial contamination of surface cultures. A better strategy is the aspiration of grains directly from an unopened sinus tract because evaluation of spontaneously extruded grains may be composed of dead organisms and contaminated bacteria. Fungi that cause eumycotic mycetoma can be difficult to grow; optimizing growth is an important step. Before being inoculated onto a culture medium, the grains should be rinsed quickly in 70% alcohol and washed several times in sterile saline to eliminate contaminating bacteria.

Biopsy specimens are preferred over discharged grains because such grains may be contaminated with surface organisms or the infecting organism may already be dead. For primary isolation, actinomycetoma grains are grown on a Lowenstein-Jensen medium and fungal grains on blood agar. Sabouraud agar without antibacterial antibiotics is satisfactory for subcultures.

Two sets of cultures are prepared: One is inoculated at 37°C and the other at 26°C. Characteristic colonies are expected to develop within 10 days. Apart from M. mycetomatis, which secretes a brown pigment in the medium, all other organisms, both bacteria and fungi, tend to maintain the color of the original grain. Bacterial colonies are usually granular or cribriform, whereas fungal colonies are either velvety or fluffy. Further identification is made by microscopic examination of fungi in a lactophenol blue preparation and of bacteria in gram and modified Ziehl-Neelsen stains. Actinomycotic granules may be white (Actinomadura madurae) , pink, red (A. pelletieri) , yellow (Nocardia asteroides, Streptomyces somaliensis) , or orange (N. asteroides) . Black granules are always eumycotic (Leptosphaeria senegalensis, Exophilia jeanselmei, Madurella grisea, M. mycetomatis) , but eumycotic granules may also be pale (Pseudallescheria boydii) .

In histologic sections stained with hematoxylin and eosin, involved tissue reveals a suppurative granuloma. Grains are seen embedded in an abscess composed of neutrophils accompanied by an outer epithelioid cell, plasma cell, and multinucleated giant cell reaction intermingled with areas of fibrosis. The size of various grains in sections is so characteristic that it allows specific diagnosis of the causative organism. Eumycetic hyphae within the grain are easy to see at ×400 magnification, whereas those of Actinomyces spp. are difficult to visualize even at ×800. In electron micrographs, concentric rings of cell wall thickening and coarse cell wall fibrils around cells are seen within eumycetic grains. When stains, cultures, and histology do not help and clinical suspicion is significant, diagnosis is achieved using a panfungal PCR and sequencing technology.

Differential Diagnosis

Tentative diagnosis is made in the presence of a chronic cutaneous and subcutaneous lesion that is swollen, indurated, and riddled with nodules, abscesses, sinuses, and fistulas that discharge granules. Grains are common to actinomycosis, botryomycosis, actinomycetoma, and eumycetoma. The linear, marching lymphangitis typical of Nocardia infection can also be seen with infections caused by Sporothrix, M. marinum, M. kansasii, Leishmania, Coccidioides, Cryptococcus, lupus vulgaris, and tularemia.

Treatment

The success of treatment depends not only on the differentiation between actinomycetoma and eumycetoma but also on definitive identification, culture, and sensitivity of the causal organism. Initial treatment of actinomycetoma is medical. Initial treatment of eumycetoma is a wide surgical debridement of acute and chronic necrotic tissues and chemotherapy.

Etiology

Syphilis was first recognized in Europe in 1495; its cause, Treponema pallidum subspecies pallidum, was identified in 1905. The advent of penicillin in the 1940s was responsible for a marked decline in syphilis in the United States and Europe. However, the number of cases reported to the CDC increased by 81% from 2014 to 2018. In 2018, men accounted for 86% of all patients with syphilis. More than half of men with incident syphilis reported having sex with men, and 42% of those men were infected with HIV.

A second, more recent epidemic in the United States has been affecting heterosexual men and women. Rates of primary and secondary syphilis among women more than doubled between 2014 and 2018. Alarmingly, the number of incident syphilis cases rose by a factor of six among women who used methamphetamine, heroin, or other injected drugs or who had sex with a person who injected drugs. The remarkable increase in the number of cases of primary and secondary syphilis among women of childbearing age is mirrored by increasing numbers of congenital syphilis cases and increasing infant mortality.

Syphilis has vast, varied, and protean clinical presentations, and Osler’s adage remains relevant: “He who knows syphilis, knows medicine.” It has often been called “the great imitator” because so many of the signs and symptoms are indistinguishable from those of other diseases. It can challenge even the most experienced clinician, and the natural history of both untreated and treated disease can be unpredictable. The illness is caused by slender, motile, spiral bacteria— Treponema pallidum. Syphilitic lesions of the hand may be congenital, primary, secondary, or tertiary.

Clinical Findings

Congenital syphilis may present as bilateral dactylitis and metacarpitis in a newborn. Syphilitic dactylitis is characterized by edema of the hands and fusiform swelling of digits. Metacarpals and phalanges show new bone formation (i.e., reactive sclerosis), bone destruction (i.e., patchy rarefaction), and periosteal new bone formation. Syphilitic dactylitis in the infant may resemble tuberculous spina ventosa. Pathologic fractures of the metaphysis can masquerade as pseudoparalysis. Syphilis should be considered in the differential diagnosis of infantile osteomyelitis.

Primary syphilis of fingers is seldom seen now and usually occurs in men who have had contact with genital or anal lesions during sexual encounters. It may be contracted by physicians when examining an infected lesion on a patient. Examination of patients, deliveries, pelvic examinations, needle punctures, and tonsillectomies are the most common procedures performed by physicians who subsequently became infected. Extragenital syphilitic ulcers in adults occur in at least 5% of primary syphilis patients and mostly affect fingers, lips, and nipples; 14% of extra genital chancres occurred during syphilitic epidemics. Tenosynovitis, inflammation of a tendon and its synovial sheath, is a rare manifestation of secondary syphilis and, if diagnosed early, is reversible. Patients may present with gradual onset of swelling and pain of the finger. It may occur several months after successful treatment of primary penile chancre. A 32-year-old HIV-infected man was diagnosed with a syphilitic ulcerating skin lesion on the upper arm. A 9-month-old HIV-positive Nigerian girl presented with blistering dactylitis of the right middle finger, and radiograph of the right hand showed autoamputation of the terminal phalanx and osteomyelitis in the middle phalanx of the third finger. In the hand, it may present as syphilitic dactylitis with generalized swelling, induration, and erythema of a finger or as a painless ulcer within 2 to 6 weeks after exposure. The lesion begins as a rapidly growing solitary nodule on the nail or nail bed, pulp, paronychium, finger, hand, or arm that soon ulcerates and appears as nodular-ulcerative chancre. Early on, the ulcer (chancre) is red and oozing ( Fig. 3.8A ). The base of the ulcer has a firm or “cartilaginous” consistency and is surrounded by erythema and scaling (see Fig. 3.8B ). Edges of the ulcer may be rounded. Paronychia may present as a “discharging horseshoe ulcer” around the nail fold or as inflammatory periungual and subungual papules. Lesions on multiple fingers can occur. A concurrent lesion on the hand and genitalia (i.e., bipolar syphilis) may or may not be present. Enlarged, painless, and nontender epitrochlear and axillary nodes are almost always palpable but may rarely be unpalpable. There is generally no fever or constitutional symptoms.

Differential Diagnosis of a Hand Ulcer

Differential diagnosis of an ulcer on the hand, in addition to syphilis (see Fig. 3.8 ), includes (in alphabetical order) anthrax (see Fig. 3.6 ), aspergillosis, Buruli ulcer, Candida albicans, cryptococcosis, leishmaniasis, herpetic ulcer, mucormycosis (see Fig. 3.25 , later), neutrophilic dermatoses (e.g., classical pyoderma gangrenosum) (see Figs. 3.10 and 3.11 , later), protothecosis, sporotrichosis (see Figs. 3.16 to 3.19 , later), tularemia, TB, and yaws. Interdigital ulcers are typical of a C. albicans infection.

Diagnosis

The majority of syphilis cases are diagnosed by means of serologic testing. The standard screening algorithm begins with a nontreponemal test (e.g., a rapid plasma reagin [RPR] or Venereal Disease Research Laboratory [VDRL] test). The reactivity is confirmed with the use of a highly sensitive and specific treponemal test (e.g., the T. pallidum particle-agglutination test or an automated enzyme or chemiluminescence immunoassay). Serologic results are nonreactive in up to 30% of persons with primary syphilis, and testing should therefore be repeated in 2 weeks if the initial test result is nonreactive. Nontreponemal test titers often decline rapidly after treatment but may also decline, although more slowly, in the absence of treatment. Treponemal tests remain reactive irrespective of the treatment history, but up to 24% of patients treated in the early stage of syphilis have seroreversion years after therapy. The RPR test may be false positive in nonvenereal treponemal infections such as yaws. Diagnosis is confirmed by dark-field microscopic examination of ulcer exudate, which almost always shows spirochetes.

Secondary syphilis may develop 4 to 8 weeks later if a primary syphilitic lesion is not treated. Clinical manifestations of secondary syphilis include a mild, nonpruritic rash, particularly on the palms and soles; fever; lymphadenopathy; mucosal lesions (e.g., mucous patches or condyloma latum); alopecia; periostitis; and occasionally hepatitis (often with high alkaline phosphatase values but minimally elevated aminotransferase levels) or nephritis. All these manifestations have a broad differential diagnosis. Primary syphilis and secondary syphilis are the sexually transmissible stages of infection. Paronychia of the finger may present during secondary syphilis. Secondary syphilitic lesions in the hand may consist of exuberant ulcerated lesions on the palms, dorsal hand, and wrist.

Early latent syphilis , an asymptomatic stage, can occur between the primary and secondary stages and can also occur after the resolution of secondary-stage lesions. In up to 24% of patients, early latent syphilis is interrupted by relapse with recurrent, infectious secondary lesions. The CDC uses a 1-year cutoff point for the duration of infection to demarcate early latent from late latent syphilis because most relapses occur within 1 year; thus syphilis may be infectious in the early latent phase or within 1 year of primary lesion.

Asymptomatic or symptomatic neurologic involvement may occur during any stage of syphilis. Primary lesion may be followed by CNS involvement in 40% of patients, of which 10% develop meningeal or meningovascular syphilis. CNS invasion by treponemes is accompanied by abnormal cerebrospinal fluid (CSF) findings in up to 50% of persons after early infection, even in the absence of clinical features. These CSF abnormalities typically resolve after recommended therapy for early syphilis. Early clinical findings (i.e., early neurosyphilis) include meningitis, often a basilar form, resulting in cranial-nerve abnormalities. Of the other 30% asymptomatic patients, some progress to tertiary neurosyphilis.

Tertiary syphilis develops after 2 to 50 years in about 30% of untreated patients. Tertiary lesions of syphilis in the hand present as gummas—nonspecific, chronic granulomatous lesions that may involve tissues from skin to bone. The skin gumma is a superficial nodule or deep granulomatous lesion that appears as a punched-out ulcer. Cutaneous gumma can occur in syphilis, yaws, and TB and all appear similar. They are exceedingly rare, and biopsy and cultures can conform diagnosis. Diagnosis is facilitated by concurrent cardiovascular or neurologic syphilis that is present in 10% of untreated patients after 10 years of onset. Of the 30% of patients that result in tertiary syphilis, gumma develops in 15%, cardiovascular in 10%, neurosyphilis in 5%, and ocular and otic syphilis in 5%. Natural history of untreated and treated syphilis has been well depicted graphically by Ghanem et al. in 2020.

Treatment

Pathologic fractures and dactylitis in congenital syphilis are treated with protective splints in addition to an appropriate dose of penicillin. Penicillin is highly effective for all stages of syphilis and is the drug of choice. Resistance to penicillin has not been observed in T. pallidum. A single dose of 2.4 million units of long-acting penicillin G benzathine, given intramuscularly, sustains treponemicidal drug levels in blood for 7 to 10 days and is effective in the treatment of uncomplicated early syphilis. Late latent syphilis is treated with a total of three doses of penicillin G benzathine, given at weekly intervals. Persons with neurosyphilis are treated with intravenous aqueous penicillin G because of the inability to achieve measurable levels of penicillin G benzathine in the CSF. The regimen for penicillin-allergic patients is doxycycline (100 mg), administered orally two times daily for 2 weeks. Doxycycline administered for 28 days is also effective for late latent syphilis in persons with or without HIV infection. As the primary lesion heals, it shrinks, skin around it peels away, and the ulcer is covered by crust. Syphilitic tenosynovectomy is treated with thorough debridement and irrigation of flexor tendon sheath and antibiotics.

Prevention

From mid-1997 to the end of 1999, there was a sexually transmitted infectious syphilis outbreak mainly in heterosexual people in British Columbia, Canada, that was concentrated in Vancouver. The rate across the province increased from less than 0.5 to 3.4 per 100,000, and the rate in Vancouver reached 12.9 per 100,000. To eliminate the syphilis outbreak by treating people at risk of infection, in 2000, a targeted mass treatment program provided azithromycin (1.8 g orally) to 4384 at-risk residents in this city. After the program, syphilis frequency fell significantly in 6 months.

In a study in Los Angeles, doxycycline administered prophylactically at a dose of 100 mg daily reduced the combined odds of syphilis, gonorrhea, and chlamydia infection by 73% in a group of 30 HIV-infected men who have sex with men. An open-label study involving 116 men who have sex with men showed that postexposure prophylaxis with doxycycline (200 mg given orally within 24 hours after a sexual encounter) resulted in a 73% reduction in the risk of incident syphilis over a mean follow-up period of 8.7 months.

Etiology and Epidemiology

Tularemia, a bacterial zoonosis, is caused by Francisella tularensis, one of the most infectious pathogenic bacteria known. It requires inoculation or inhalation of as few as 10 organisms to cause disease. F. tularensis is a small, nonmotile, aerobic, gram-negative coccobacillus.

Rabbits, hares, and rodents are especially susceptible. Humans can become infected through several routes, including tick and deer fly (i.e., yellow fly) bites, skin contact with infected animals, ingestion of contaminated water, laboratory exposure, and inhalation of contaminated dusts or aerosols. In addition, humans can be exposed as a result of bioterrorism. In the United States, naturally occurring infections have been reported in all states except Hawaii.

Clinical Presentation

The main form of this disease is ulceroglandular (70%), usually occurring after a tick or deer fly bite or after handling of an infected animal. A skin ulcer appears at the site where the organism entered the body. The ulcer is accompanied by swelling of regional lymph glands, usually in the armpit or groin. Untreated, the disease may progress to include a moderate to high fever, inflammation of the face and eyes, ulcerating lymph nodes, extreme fatigue, loss of appetite, and sepsis; in approximately 1% of cases the disease is fatal.

Diagnostic Testing

Growth of F. tularensis in culture is the definitive means of confirming the diagnosis of tularemia. Appropriate specimens include swabs or scrapping of skin lesions, lymph node aspirates or biopsies, pharyngeal washings, sputum specimens, or gastric aspirates, depending on the form of the illness. Paradoxically, blood cultures are often negative.

Physicians who suspect tularemia should promptly alert the laboratory about the need for special diagnostic and safety procedures. Rapid diagnostic testing for tularemia is not widely available, and help from the CDC should be sought; check its website for current contact information.

A presumptive diagnosis of tularemia may be made through testing of specimens using direct fluorescent antibody, immunohistochemical staining, or PCR. The diagnosis of tularemia can also be established serologically by demonstrating a fourfold change in specific antibody titers between acute and convalescent sera. Convalescent sera are best drawn at least 4 weeks after illness onset; thus this method is not useful for clinical management.

Treatment

Streptomycin is the drug of choice. Tetracyclines may be a suitable alternative for patients who are less severely ill. Tetracyclines are static agents and should be given for at least 14 days to avoid relapse.

Etiology and Epidemiology

Yaws is an infectious, chronic, relapsing, nonvenereal, treponemal disease caused by Treponema pallidum spp. pertenue (T. p. pertenue) . It is transmitted by direct skin contact with the contagious exudate of an exposed and infected skin lesion. About 75% of those affected are children under 15 years of age, and the peak incidence occurs in children 5 to 10 years old. It is endemic in tropical regions of the world. Humidity and constant warm temperatures are necessary for the treponema to flourish. It occurs “where the highways end,” and there is poverty, overcrowding, low levels of collective hygiene, poor sanitation, scanty clothing, and minimal health care, all of which facilitate the spread of yaws. Many areas of Africa, Southeast Asia, South America, and Oceania are included, and any area of exposed skin is at risk. Yaws is categorized into early and late stages of infection; early yaws consist of the primary and secondary stages and late yaws consists of the tertiary stage.

Clinical Findings

The primary yaws lesion arises in the skin at the site of inoculation. It usually appears 9 to 90 days (average, 21 days) after inoculation and begins as an erythematous papule that turns into a nodule(s) or papilloma(s). Nodules and papillomas subsequently enlarge into highly infectious, raspberry-colored, friable ulcers containing numerous Treponema. The lesions may be multiple and bilateral. At initial presentation, papilloma is more common (80%) than the ulcerative lesion (20%). This ulcerative lesion, also called mother yaws, usually heals spontaneously after several weeks to months, leaving an atrophic scar. Bone lesions in the form of osteoperiostitis are common and occur in numerous bones simultaneously including hand bones in early stages of yaws.

The secondary stage of infection typically occurs weeks to months after the appearance of mother yaws. Secondary lesions (called daughter yaws) are smaller than mother yaws but are more widespread. They exude highly infectious serum. The soft tissue skin and subcutaneous lesion eventually invades bone and cartilage. The striking feature of secondary yaws is osteoperiostitis, involving the phalanges, metacarpals, and forearm bones. Periostitis occurs with increased bone density, sclerosis, thickening, and enlargement of the cortex and an increase in the width of the entire shaft ( Fig. 3.9 ). Proximal, middle, and distal phalanges are involved in yaws dactylitis in that order of frequency. Tender and fusiform or spindle-shaped soft tissue and bone swelling of fingers and metacarpals is a characteristic clinical presentation in secondary yaws. It may be bilateral and symmetric with considerable finger, hand, and forearm pain. Yaws osteoperiostitis is similar clinically to osteoperiostitis in tuberculous, syphilitic, blastomycotic, and brucellosis dactylitis.

Tertiary lesions appear after a latency period of 5 to 10 years in 10% of the cases. Contractures of fingers are reported among the population of West Africa due to yaws. Gummas may involve skin and subcutaneous tissues over areas of underlying osteitis. Nodules may develop in the vicinity of joints. “Ghoul hand” is a condition seen among black people in Africa, probably a manifestation of tertiary yaws, marked by depigmentation of the palms and contraction of the skin that a claw-like and corpse-like appearance to the hands. The disease is rarely fatal; however, without treatment it can lead to chronic disfigurement and disability.

Diagnosis

The diagnosis of yaws is primarily based on clinical findings in an epidemiologic context. A painless ulcer, in a child younger 15 years who lives in an endemic area or who has immigrated from an endemic area, may be diagnosed as yaws. Morphologic and serologic tests are identical to those for syphilis and are used to diagnose yaws as well. The clinical diagnosis can be confirmed by examining a sample of serum from an ulcerative skin lesion under a microscope with dark field examination. A VDRL test, RPR test, a fluorescent treponemal antibody absorption test (FTA-Abs), an agglutination assay for antibodies to T. pallidum (TPHA), and a microhemagglutination assay for T. pallidum (MHA-TP) can be done and are positive for yaws the same as for syphilis.

Treatment

Penicillin remains the drug of choice. Yaws can be treated with a single dose of benzathine penicillin injection, which cures both the early and late versions. Relapse is very rare. The dose for adults is 1.2 million units and for children younger than 10 years old is 600,000 units. Resistance to penicillin has emerged in rare cases. For those who are allergic or resistant to penicillin, tetracycline, erythromycin, and doxycycline can be used. Spirochetes are usually not detectable by dark-field microscopy within 8 to 10 hours of treatment, and the lesions resolve in 90% of cases within a month. However, 25% of children show clinical and/or serologic evidence of either relapse or reinfection within 2 years. A resurgence of yaws has been occurring since around the year 2000 in western and central Africa and the Pacific Islands. The finding that a single oral dose of azithromycin (30 mg/kg) was as effective as benzathine benzylpenicillin has prompted a renewed interest by the World Health Organization (WHO) in 2012 toward eradication of this infection. Gonzalez-Beiras, who previously reported the excellent response to benzathine benzylpenicillin therapy for yaws osteoperiostitis, has now documented a confirmed case of yaws with osteoperiostitis successfully treated with a single-dose azithromycin.

Etiology and Epidemiology

Neutrophilic dermatoses are ulcerative dermal diseases in which the ulcer edges are full of neutrophils. Su et al. classified ulcers of neutrophilic dermatoses into four types: (1) pyoderma gangrenosum (PG), the classic ulcerative PG ; (2) bullous or atypical PG ; (3) pustular PG ; and (4) vegetative PG. The ulcerative classic form is the most common and the pathognomonic lesion is an ulcer with purplish overhanging border. PG is a progressive, necrotizing, noninfectious, autoimmune, and ulcerative dermatosis that commonly mimics an acute or chronic infection. It is an indicator of an underlying immunologic or inflammatory bowel disease (ulcerative colitis, Crohn syndrome) in more than 50% of cases.

PG, the classic ulcerative PG, was first described as a fulminant streptococcal infection, but it has subsequently been proved to be a noninfectious ulcer. It is more common in the lower limbs (70% to 80%) and rare in the hands and upper extremity (16%). Only 20 cases in the hand and upper extremity were reported in the English literature between 1983 and 2001; all were misdiagnosed initially as infections. Since then the condition has been classified under ulcerative neutrophilic dermatoses. The prevalence of PG in ulcerative colitis is about 5%, and in Crohn syndrome it is about 2%.

Bullous or atypical PG is associated with hematologic neoplasms (i.e., myeloproliferative diseases such as acute myeloid leukemia, hairy cell leukemia, and myelodysplastic syndrome) in 70% of cases. Miyata et al. reviewed 17 cases of bullous PG that have been reported over 20 years, from 1991 to 2011. Unlike the reddish or violaceous halo of classic PG, bullous PG has bulla and bluish-gray halo surrounding the ulcer.

Pustular PG is associated with arthralgia, inflammatory bowel disease, and monoclonal gammopathy in 70% of cases. It is considered a forme fruste of ulcerative PG in which pustules do not evolve into frank ulcers. Histologically, it shows pustular vasculitis. Acute febrile neurophilic dermatosis is called Sweet syndrome. When bullous PG, pustular PG, and bullous Sweet syndrome occurred on the dorsum of both hands, Galaria called it “neutrophilic dermatosis of the dorsal hands” in 2000, and reports of more than 100 cases since then have validated this condition.

Vegetative PG is the most benign, localized, and nonaggressive form of PG and is not associated with systemic diseases, has superficial verrucous and ulcerative lesions, has a granulomatous histologic appearance, and responds to minor treatment measures that do not require corticosteroids in most cases. Mixed types of PG also occur, showing that different forms are part of a single clinical spectrum from the nonaggressive vegetative PG to the rapidly destructive classical PG. In all cases, the margin of the ulcer is packed with “noninfectious” neutrophils. In 25% of patients with a generalized category of neutrophilic dermatoses, no known underlying medical condition was found.

Clinical Findings

Neutrophilic dermatoses may affect periungual region of fingers, the dorsal surface of a single finger, rarely multiple fingers, palm, hand ( Fig. 3.10 ), wrist, forearm, elbow, or upper arm and chest ^, ( Fig. 3.11 ). When it occurs on the dorsum of the wrist, without intervention, inflammatory process may deepen and destroy the wrist joint. Patients are most often between their third and fourth decades and 4% are children. A centrifugally creeping and weeping ulcer is surrounded with a rough, serpentine, undermining, burrowing, black-blue, violaceous, or gunmetal gray border, which is further encircled by a 5- to 10-mm rim of raised purplish erythema and covered by a thin, translucent graying epidermis (see Fig. 3.10A ). It spreads 1 to 2 cm/day in a centrifugal pattern. Pain is a significant symptom in 75% of cases. The central portion undergoes wet and gangrenous necrosis, oozes, and impersonates infection. It may cause digital ischemia. Atypical PG of the dorsal hand may mimic SCC. PG does not respond to traditional antibiotics or surgical intervention. It is surgical intervention without immunosuppression that makes it worse. Under immunosuppressive protection, necessary surgery may be undertaken.

Diagnosis

Neutrophilic dermatosis (mostly characterized by PG) is a clinical diagnosis, and a high clinical suspicion prompts correct diagnosis and nonsurgical treatment. If it is on the dorsum of both hands, the condition is designated as “neutrophilic dermatosis of dorsal hands” ( Fig. 3.12 ) and may extend into the fingers ( Fig. 3.13 ) If after debridement of a supposedly infected wound (with pustules, bullae, or ulcerations) there is no improvement but there is centrifugal extension of the lesions with a “sepsis-like” syndrome and persistent negative cultures, PG is highly probable; in that case, corticosteroids (not antibiotics) are the definitive treatment. Rarely, PG may masquerade as necrotizing fasciitis or herpetic ulcer. PG ulcers appear similar to other cutaneous ulcers, such as aspergillosis, and may lead to misdiagnosis.

Biopsy is of limited diagnostic value as it accelerates the ulcerative process; however, in cases where biopsy is done, “a sea of neutrophils” are characteristic in the marching edge of the ulcer. No laboratory test is confirmatory. In a clinical setting, when an ulcer does not yield infectious organisms and biopsy aggravates the ulceration, a diagnosis of PG is paramount. Dermal neutrophilia in the advancing border of the ulcer confirms that diagnosis.

In a review of 13 cases in the literature and 7 cases added by Huish and colleagues, every patient initially had a misdiagnosis of infection. In a later review of 35 cases of the hand by Wong, 29 cases were initially treated for infection and 13 cases were debrided with further deterioration of ulceration. Thirteen misdiagnoses in Huish and colleagues’ series resulted in 16 unnecessary surgeries, including 2 failed skin grafts and 4 amputations. No surgical procedure resulted in clinical improvement, and all were followed by unrelenting extension of the ulcer. Five physicians on an average examined each patient before the final diagnosis of PG was made by a dermatologist. Clinical improvement after correct medical treatment with oral prednisone, azathioprine, or dapsone was dramatic and occurred within a week.