Gorgas Case of the Week - 2019 Series

University of Alabama at Birmingham

Gorgas Case 2019-02

Universidad Peruana Cayetano Heredia
The following patient was seen in the outpatient clinic of the Infectious Diseases Department of the Hospital Cayetano Heredia during the Gorgas Diploma Course.
Image for Case 2019-02
History: A 58-year-old previously healthy male farmer, states that 1 month prior to presentation, while working with wooden logs, he embedded his left thumb with a spike. The site ulcerated and started draining and in subsequent days, he noted the presence of multiple nodules and erythema in the left forearm. Lesions were small, nodular and painless with spontaneous suppuration in some. He received a course of oral antibiotics followed by a topical anti-fungal cream without any improvement.

Epidemiology: Born and resides in Ancash (highlands) with recurrent trips to Lima. He works as a farmer and breeds several animals including dogs, cats, cattle, pigs, chickens, guinea pigs. Past medical history is non-contributory.

Physical Examination: A small ulcer with spontaneous serous drainage is present in the left thumb. Erythema and edema of the left thumb and thenar eminence are shown [Image A]. In the lateral left forearm, there are several erythematous subcutaneous nodules [Image B], some of them are painful and crusted.

Laboratory: Hemoglobin 14g/dl; WBC 6500 with normal differential; Glucose 90 mg/dl, normal liver function tests.

UPCH Case Editors: Carlos Seas, Course  Director / Carlos McFarlane, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director

Diagnosis: Lymphocutaneous sporotrichosis due to Sporothrix schenkii
Images for Case 2019-02
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Discussion: Sporothrix schenkii was cultured [Image C] from an aspirate of one of the nodular lesions on the left forearm and from the border of the ulcer. The colonies are moist and glabrous, with a wrinkled and folded surface, pigmented colonies can be seen from white-cream to black. A sample of the colonies showed the typical characteristic bouquet-like micro conidia [Image D].

In cultures of scrapings, aspirates or biopsy material on Sabouraud’s agar, S. schenkii grows very easily and rapidly when present. Smears or aspirates from the lesions in sporotrichosis are usually negative on direct examination (not done in this case) and no useful serology is available. Giemsa stain from the aspirates was negative for Leishmania, skin test for leishmania (Montenegro´s test) was also negative.

The differential diagnosis of nodular or ulcerated lesions in Perú with or without lymphocutaneous spread includes leishmaniasis, sporotrichosis, atypical mycobacteria, and nocardiosis. Sporotrichosis is always an important consideration in areas such as Perú even where leishmaniasis is much more common. In normal hosts, lymphocutaneous lesions on an extremity would be the most common presentation of sporotrichosis [see Gorgas Case 2008-01 and Gorgas Case 2014-10, PLos ONE 2015; 10(6):e0127924, Am J Trop Med Hyg 2018 Dec 26. doi: 10.4269/ajtmh.18-0667]. Extracutaneous manifestations of sporotrichosis include osteoarticular, meningeal, and pulmonary sporotrichosis. These are usually seen in immunocompromised hosts and in alcoholics. In the last two decades a systemic presentation restricted almost exclusively to HIV patients has been described [see Gorgas Case 2011-02].

Environmental reservoirs for S. schenkii include sphagnum moss (including wood or plants contaminated by moss), decaying vegetation, hay, soil and masonry. Outdoor work including farming, construction, gardening, and having a cat are risk factors [Clin Infect Dis.2004;38(4):529-35 and Clin Infect Dis. 2003;36(1):34-9]. Acquisition is generally by local inoculation. Sporotrichosis is distributed worldwide but most cases are reported from the Americas and Japan. Most cases are sporadic or occur in self-limited clusters due to some point source exposure. The area around Abancay, Perú (not where this patient lives) has been, perhaps uniquely, identified as an area where sporotrichosis is not only entrenched but is hyperendemic with annual incidence rates of up to 60 per 100,000 population [Clin Infect Dis.2003;36(1):34-9; Clin Infect Dis. 2000;30(1):65-70 and Int J Dermatol 2017;56(10):1037-45].

Guidelines for treatment of sporotrichosis have been released by the Infectious Diseases Society of America [Clin Infect Dis.2007;45(10):1255-65] and are partly based on work from our Institute. The treatment of choice for lymphocutaneous sporotrichosis is itraconazole, and in severe extracutaneous or disseminated disease, amphotericin B can be used. Terbinafine 500-1000 mg po bid has been shown to be effective therapy [Mycoses. 2004;47(1-2):62-8]. Posaconazole is the only newer azole to have good in vitro activity against S. schenckii. Fluconazole at higher doses (400-800 mg daily) has demonstrated some activity for lymphocutaneous sporotrichosis, but voriconazole, ravuconazole and the echinocandins are ineffective against S. schenckii though some are active against other Sporothrix species.

In the reality of poor countries, many patients cannot afford itraconazole or terbinafine. The older but still effective mode of therapy with a saturated solution of potassium iodide (SSKI) is still widely used in practice. SSKI and its clinical use has been reviewed [J Am Acad Dermatol. 2000;43(4):691-7] and we have previously demonstrated the utility of once daily dosing in order to increase compliance [Pediatr Infect Dis J. 1996;15(4):352-4]. The mechanism of action is unknown. SSKI can also be used for entomophthoromycosis caused by Basidiobolus and Conidiobolus. In dermatologic practice SSKI can be used for erythema nodosum, nodular vasculitis, erythema multiforme, and Sweet’s disease. The main adverse effects are gastrointestinal (nausea) and the SSKI can be added to larger volumes of water, juice, or milk for administration. Care must be taken to avoid potassium or iodide toxicity in patients on ACE inhibitors or potassium sparing diuretics, in patients with renal disease, and in patients on medications or with conditions making them unable to autoregulate thyroid hormone production. In areas with high rates of iodine deficiency, such as the Andean highlands, the use of this solution can trigger hyperthyroidism (Jod-Basedow disease).

This patient was started on itraconazole 200mg/day with a plan for at least 3 months of treatment.

University of Alabama at Birmingham

Gorgas Case 2019-01

Universidad Peruana Cayetano Heredia
The Gorgas Courses in Clinical Tropical Medicine are given at the Tropical Medicine Institute at Cayetano Heredia University in Lima, Perú. For the 19th consecutive year, we are pleased to share interesting cases seen by the participants that week during the February/March course offerings. Presently the 9-week Gorgas Course in Clinical Tropical Medicine is in session. New cases will be sent by e-mail every Tuesday/Wednesday for the next 9 weeks. Each case includes a brief history and digital images pertinent to the case. A link to the actual diagnosis and a brief discussion follow.
Carlos Seas and German Henostroza
Course Directors
The following patient was seen in the Tropical Medicine Outpatient Clinic at the Cayetano Heredia Hospital in Lima, Peru during the Gorgas Diploma Course 2019.
Image for Case 2019-01
History: A 72-year-old male, previously healthy, presented with a 5-6-year history of right-hand weakness that impaired daily activities. Two years earlier, the patient noticed several, small, circular erythematous lesions on the skin of the abdomen. Lesions were non-pruritic nor painful. During this period, the patient noticed progressive numbness and decreased sensation of the forearms, hands, knees and right foot. He also had an episode of, inadvertently stepping on hot coals and burning his right sole. He denied nasal symptoms as congestion and nosebleeds, and edema of feet.

Epidemiology: Lifelong farmer born and lives in Moyobamaba (San Martin, high jungle). No contact with persons with similar lesions. No known TB contacts. No HIV risk factors.

Physical Examination: BP: 110/70mmHg. HR: 74. RR 15. Afebrile. No apparent distress. Areas of infiltrated skin with indistinct borders on the upper limbs and trunk [Image A] were seen, as well as multiple small and circular plaques [Image B] extending as far as his thighs and buttocks, and separately a large punched-out plaque was seen over the left scapula and posterior forearm [Image  C]. Sensation is impaired in all skin lesions including the center of the large plaque. There is thickening of several peripheral nerves, in particular, the right ulnar and the common peroneal nerves. There is anesthesia in both hands and the right foot, as well as hypoesthesia in the left foot. Additionally, there is weakness in muscles innervated by both ulnar nerves and clawing of the right 5th finger [Image D]. The face appeared normal. Rest of the physical exam is unremarkable.

Laboratory: Serological tests for Hepatitis B, C, Syphilis and HIV were negative.

UPCH Case Editors: Carlos Seas, Course  Director / Carlos McFarlane, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director

Diagnosis: Leprosy (Hansen´s disease) Mycobacterium leprae. Multibacillary leprosy according to the WHO classification. Borderline Lepromatous (BL) leprosy according to the Ridley-Jopling classification.
Images for Case 2019-01
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Discussion: The patient consented to a skin biopsy only from the lesion shown in Image B. Histopathology showed normal epidermis and beneath, in the dermis, there is a dense inflammatory infiltrate, nodular and linear, which is both superficial and deep, and is composed of lymphocytes and foamy histiocytes. The linear infiltrates follow nerve tracts and skin appendix structures [see black arrow in Image E]. The Fite-Faraco AFB stain shows multiple acid-fast bacilli compatible with Mycobacterium leprae [Image F].

These biopsy findings are compatible with borderline lepromatous leprosy when leprosy is classified precisely in the immunologic sense using the traditional Ridley-Jopling classification. This is a spectrum of disease ranging from tuberculoid leprosy (TT) with no AFB in lesions and good cell mediated immunity, to lepromatous leprosy (LL) with many AFB and poor cell-mediated immunity (CMI). In between are the borderline leprosy (BL) patients, borderline tuberculoid (BT) near the tuberculoid end, mid-borderline (BB) in the middle, and borderline lepromatous (BL) near the lepromatous end of the spectrum. The CMI decreases and bacillary load increases as the spectrum goes from TT to LL. Leprosy is a disease of peripheral nerves and skin. Leprosy can be diagnosed clinically in any patient with simultaneous skin lesions and sensory loss over the lesions unless there is hyperkeratosis. However, in early lepromatous cases, sensation is normal over the lesions. Thus, with loss of sensation, a diagnosis of leprosy can be made; with intact sensation, the diagnosis is possible but must be confirmed in some other way. This patient seemed to have three different types of lesions simultaneously: areas of infiltrated skin, multiple small plaques and a large punched-out lesion. Areas of infiltrated skin are characteristic of lepromatous leprosy, areas of innumerable small plaques are characteristic of borderline lepromatous, and the punched-out lesions are characteristic of mid-borderline (BB) leprosy. The polar types of leprosy, TT and LL, are immunologically stable, their CMI never changes, whereas the borderline types are immunologically unstable, their CMI may change over time, they may lose or gain CMI, so their clinical characteristics may change. This patient could have started his illness many years ago somewhere between BT and BL (most skin lesions are compatible with BL), and then decreased his CMI and presented some lesions that resemble early LL, but without other features of LL like nasal symptoms, swelling of feet and facial involvement.

For the purposes of determining treatment, the usual and most practical grading system is the WHO classification. For choosing the regimen, it matters only whether the patient has paucibacillary or multibacillary disease. Where no slit skins smears (a test in which a sample of material is collected from a tiny cut in the skin and then stained for M. leprae) can be done, paucibacillary leprosy is defined as five or fewer skin lesions; multibacillary cases have six or more lesions. Paucibacillary disease usually presents with small numbers of hypopigmented macules or erythematous plaques with absent or reduced sensation and well-demarcated borders. Multibacillary disease is usually widespread at diagnosis with multiple plaques or infiltrated areas of skin with indistinct borders that are often non-anesthetic, and papules or nodules.

The standard WHO regimen for paucibacillary disease is 100 mg dapsone a day unsupervised and 600 mg rifampin once per month directly observed for 6 months. For multibacillary disease, the long-standing recommendation is for patients to receive 100 mg dapsone and 50 mg clofazimine a day unsupervised and 600 mg rifampin and 300 mg of clofazimine directly observed once per month. A standard WHO multibacillary dose-pack (provided free to endemic countries) is shown [Image G]; the instructions in English must be clarified for all healthcare staff and patients. WHO now recommends only 1 year of therapy for multibacillary cases [controversy discussed in Lancet. 2004 Apr 10;363(9416):1209-19], but some would treat those with high bacterial indices (4 to 6+) for the previously recommended 2 years due to higher relapse rates.

For multibacillary disease in the USA and some other developed countries where the cost of rifampin is not limiting, the recommended first line regimen has for many years been 100 mg dapsone, 50 mg clofazimine, and 600 mg rifampin daily for 24 months. No comparative clinical or follow-up data on the different dosing regimens has been published and both are highly effective. However, many patients object to the severe cutaneous pigmentation that results from clofazimine therapy [see Gorgas Case 2005-04] and in the USA minocycline 100 mg/day in place of clofazimine is accepted as an alternative. However, evidence of the efficacy of minocycline’s anti-inflammatory activity against Type 2 reactions (see below) is not as substantial as the evidence for clofazimine. In adults, ofloxacin (400 mg/day) and clarithromycin (500 mg/day) are also sometimes used as a substitute for clofazimine in multi-dose regimens.

This patient, being multibacillary, will be treated with the multibacillary regimen recommended by WHO. The possibility of adverse effects of dapsone and clofazimine, or of a lepra reaction should always be explained to a patient who is starting treatment and a reference text should be consulted prior to initiation of therapy by anyone not familiar with these. The most common reaction in multibacillary disease, occurring in about 50% of patients with lepromatous and borderline lepromatous leprosy is a Type 2 reaction, which has as the most common presentation erythema nodosum leprosum (ENL). ENL is a vasculitis at the site of any deposit of dead and disintegrating M. leprae, often accompanied by a severe systemic illness, and characterized by high levels of tissue and circulating TNF-alpha. ENL presents with fever together with many tender erythematous nodules [see Am J Trop Med Hyg. 2006;74(5):868-79]. ENL may also produce to varying degrees, neuritis, uveitis, myositis, dactylitis, periostitis, orchitis, lymphadenitis and nephritis accompanied by edema, arthralgia, and leukocytosis. ENL may occur in patients prior to therapy, during therapy and/or after therapy until the antigen load decreases markedly. ENL may present as repeated acute episodes or may be chronic and ongoing. ENL can be treated symptomatically if mild or with prednisone or thalidomide if severe [see Gorgas Case 2011-04].

In endemic areas, we usually examine the family contacts once a year for at least five years, and advise them to contact the health system in case they present any skin lesion or numbness