Gorgas Case of the Week - 2019 Series

 
University of Alabama at Birmingham

Gorgas Case 2019-09

Universidad Peruana Cayetano Heredia
The Gorgas Course in Clinical Tropical Medicine 2019 spent its last week with a 4-day field trip to Iquitos, Peru on the banks of the Amazon River. Iquitos, with a population of approximately 450,000, is the largest city in the world that is reachable only by air or by river. The nearest road ends over 400 km away. The following patient was seen in the inpatient service of Regional Hospital of Loreto. We would like to thank Dr. Isela Machaca, and our Pathologists at Cayetano Heredia Hospital, Dr. Jaime Cok and Dr. Yessenia Salas for their contribution in presenting this case.
Image for Case 2019-09
History: A 66-year-old male patient was admitted with an 8-month history of hoarse voice and odynophagia initially to solid food but also to liquids. The patient noticed an extensive lesion on the palate and significant weight loss for which decided to attend the hospital for further advice.

Epidemiology: Born and lives in Iquitos. Works as a farmer. He states that he had a painless ulcerative lesion on the left leg in 1969 while staying in Brazil, that he cured himself by applying battery acid (Image A). At that time the ulcer healed in one month with no further relapse. In 2014, he developed erythematous lesions on the nasal mucosa that were presumptively diagnosed as rhinoscleroma and treated locally with antibiotics and surgical debridement resulting in septal perforation and gross nose deformity. In addition, he states that he had two episodes of malaria in 1988.

Physical examination: Temperature 36.5C; BP: 100/60; pulse 67; respirations 20; body weight 60Kg

Gross deformity of the nose with septal perforation was found (Image B); gross granulomatous tissue infiltrating the hard and soft palate with no bleeding (Image C); absence of uvula; infiltration on the larynx including the epiglottis and vocal cords. A hypochromic lesion located on the left leg was appreciated, but no regional adenopathy.

Laboratory result at admission: Hemoglobin 10.g g/dl; WBC 11,840 (0 bands, 77% neutrophils, no eos); glucose 82 mg/dl; creatinine 0.91 mg/dl.
HIV non-reactive; VDRL non-reactive; HTLV-1 non-reactive; total core positive for HVB (further studies pending).
Normal chest x-ray.
Stool for ova and parasites: negative

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

Diagnosis: Mucosal leishmaniasis
Images for Case 2019-09
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Discussion:
Biopsies were taken from the palate lesion. The pathology reported the presence of a dense inflammatory infiltrate mainly composed of histiocytes and lymphocytes. Several rounded structures were observed inside the histiocytes compatible with amastigotes, some of them disclosed a typical kynetoplast (Image D). PCR to further characterize the species is pending.

L. braziliensis is the most likely Leishmania species present in the area of the jungle where he lived at the time of his initial infection. However, in South America, it is important to definitively distinguish Leishmania species that cause only cutaneous disease (e.g., L. peruviana in Perú) from the mucocutaneous species. Both typically cause one or a few initial skin lesions that are ulcerative but painless in nature and that usually spontaneously heal over time. However, with L. braziliensis (the mucocutaneous species), severe destructive recurrence may occur in the mucosal surfaces of the naso- and oropharynx from months to years after treatment or healing of the skin ulcers. L. braziliensis only occurs in the Americas and is the only Leishmania species that causes mucocutaneous disease. In this part of the world, the vector is the Lutzomyia sandfly.

The major differential diagnosis in Perú of these oro-pharyngeal lesions would be paracoccidioidomycosis, carcinoma, or lymphoma. This would be an atypical presentation for TB. In Perú leishmaniasis would be by far the most common. The painless nature of the mucosal lesions despite widespread destruction of tissue, involvement of the mucosa, as well as spread to the larynx are consistent only with leishmaniasis. A search for the scar of the original cutaneous lesion, often subtle, usually on a limb, is a key part of the physical examination. Its absence should lend doubt to the impression of leishmaniasis. In general, oral lesions of paracoccidioidomycosis are painful, are frequently friable and bleed on contact, and gingival and buccal mucosa are frequently involved. Gingiva and buccal mucosa are less often involved in leishmaniasis making this case atypical. The lungs are the primary site of infection in paracoccidioidomycosis and the x-ray is generally abnormal. KOH preps of direct scrapings will be positive in up to 90% of cases of paracoccidioidomycosis with oral lesions. The presumptive diagnosis of rhinoscleroma in this patient is doubtful in light of the clinical evolution.

Distinguishing L. braziliensis from L. peruviana had for many years involved laborious culture techniques followed by electrophoretic isoenzyme analysis. Investigators at our Institute have now published PCR assays using both tissue as well as less invasive specimens [PLoS One. 2011;6(10):e26395; Clin Infect Dis. 2010 Jan 1;50(1):e1-6] for distinguishing the 2 species from cutaneous and mucosal lesions. Early identification of the species that causes the initial cutaneous infection would greatly help to prevent mucocutaneous leishmaniasis because it would allow more aggressive treatment and follow-up. In Perú L. peruviana (cutaneous disease only) occurs only in the high Andes; L braziliensis occurs only in the jungle and in the Amazon.

Recommended standard therapy for limited mucocutaneous disease that does not extend beyond the uvula is often 28 days of a pentavalent antimonial (sodium stibogluconate 20mg/kg/d). In our Institute, we usually begin with amphotericin B in cases of mucosal involvement when extension is beyond the uvula, as in this case. Patients are given pre- and post-treatment hydration and supplemental potassium with daily doses given in an outpatient infusion therapy setting. Liposomal amphotericin may be used in resource-rich settings, but based on limited trials it is not better in terms of efficacy even if less toxic and more convenient. Oral miltefosine is also an alternative, but failures, toxicity and the need for larger trials limits its use. On ENT examination the patient was found to have laryngeal involvement defining it as a severe case [see Gorgas Case 2010-01]. Response is expected to be slow, with the expectation of an 80% cure rate at the end of 6-week course (25 mg/kg total dose) of Amphotericin B 6 days per week as an outpatient. For severe refractory cases, the duration of amphotericin B is extended; therapy needs to be individualized. Parasite loading may be a biomarker of treatment success in mucosal leishmaniasis [Am J Trop Med Hyg 2016;94:107]. Clearly, new treatment alternatives are needed [Rev Soc Bras Med Trop 2018;51:120].
 
 
University of Alabama at Birmingham

Gorgas Case 2019-08

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. We would like to thank Dr. Sachita Sha for her contribution in preparing this case for presentation.
Image for Case 2019-09
History: 34-yo female presents with a 6-day history of fever, headaches, joint pain, and mucosal bleeding. The patient refers that upon returning from a one-month trip to Iquitos, she presented with fever and chills associated with myalgia and intense headache. Six days prior to admission, symptoms persist and retro orbital and joint pain ensues. Fever persisted and two days prior to admission, the patient presented an episode of epistaxis and complained of diffuse abdominal pain. On the day of admission, the patient noted gingival bleeding and a erythematous rash in the back.

Epidemiology: She was born in San Martin (jungle) and resides in Lima. Travel history: San Martin in December, 2018, and Iquitos (Jungle) in January, 2019. She works as a zootechnician. No known TB contacts.

Physical examination: Temp: 37 °C; RR= 18; HR=83; BP=89/66
Multiple ecchymosis in forearms and thighs. Morbilliform rash in the back and lower limbs [Image A]. No jaundice. No signs of bleeding in mucosal membranes. There was pain with palpation in the right upper quadrant, positive Murphy´s sign. No hepatomegaly. Rest of the examination is normal.

Laboratory result at admission: Day 1: Hb 12.8 g/dl; Hct 39%; WBC: 3600 (N: 52 L: 27.4 M: 14.3 B: 4.6 E: 1.7 Atypical lymphocites: 4); platelets: 46 000.; glucose: 95 mg/dl; creatinine: 0.7 mg/dl; albumin: 3.4 g/dl; ALT: 56 IU/l; AST: 118 IU/l; alkaline phosphatase: 62; INR: 0.91
Day 3: Hb 11.4 g/dl; Hct 36%; WBC: 3.200 (N: 30 L: 43 M: 18 B: 0 E: 02); platelets: 30 000.
Day 6: Hb 11.8 g/dl; Hct 36%; WBC: 3.200 (N: 52.9 L: 27 M: 15.5 B: 2.2 E: 2.4); platelets: 160 000
Thick blood film for malaria: negative
Abdominal ultrasound: edematous thickening of the gallbladder wall and free laminar fluid in the Morrison´s space [Image B]

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

Diagnosis: Dengue with warning signs
Images for Case 2019-08
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Discussion:
PCR was positive for serotype 2. In acute dengue, virus may be isolated from blood; PCR of blood will be positive, or NS1 antigen may be detected in the blood during the first 5 days only. IgM elevations do not occur until 5 days or more, so a sample taken earlier may be negative. Four-fold elevations of IgG on acute and convalescent serum may be required to confirm diagnosis.

Dengue infections range from asymptomatic through a range of clinical manifestations to death. The incubation period of this flavivirus is normally 3–7 days from the time of the infective bite of the Aedes mosquito and 14 days at the most. After the incubation period, the illness begins abruptly and is followed by the three phases – febrile, critical and recovery [Lancet 2019;393:350]. Typical dengue fever is manifest by frontal headache, retro-orbital pain, muscle and joint pain, nausea, vomiting and rash. The febrile phase lasts 2–7 days.

Malaria, other arboviruses, leptospirosis, rickettsial disease, measles, rubella, or typhoid may present similar findings in the pre-rash phase of infection and need to be tested for. Mild elevations of liver function tests are typical of dengue as well as the other diseases mentioned. The morbilliform rash is similar to that found in rubella, which needs to be considered in inadequately immunized patients. An early flush-like rash often occurs (not present here) and wanes after a few days to be replaced by the morbilliform rash as occurred here. A late petechial rash may also occur. If symptoms begin more than 2 weeks after a patient has left an endemic area dengue can be essentially ruled out.

When the temperature drops to 37.5–38.0ºC or less and remains below this level – usually on days 3-7 of illness – an increase in capillary permeability in parallel with increasing hematocrit levels may occur, and marks the beginning of the critical phase when it occurs (though not in this case) [see Gorgas Case 2011-09 for an example]. This period of clinically significant plasma leakage usually lasts 24–48 hours.

Plasma leakage, hemoconcentration and abnormalities in homeostasis characterize severe dengue when it occurs. The mechanisms leading to severe illness are not well defined but the immune response, the genetic background of the individual and the virus characteristics may all contribute to severe dengue. Mild bleeding such as epistaxis or mucosal bleeding by itself is not enough to classify a patient as severe dengue. Increasingly, small pleural effusions are recognized in dengue by ultrasound but are not indicative of severe plasma leakage unless there is respiratory compromise.

Primary infection by any of the four virus serotypes (DEN 1-4) is thought to induce lifelong protective immunity to the infecting serotype. Sero-epidemiological studies in Cuba and Thailand consistently support the role of secondary heterotypic infection (with another serotype) as a risk factor for severe dengue, although there are a number of reports of severe cases associated with primary infection, which may be a reflection of viral virulence factors.

Dengue was reported in Perú for the first time in 1990; since then, all four serotypes are circulating, mainly along the north coast and the jungle. In 2014, DEN-2 has been predominant in the Iquitos area; it was isolated in 2011 for the first time and appears to be persisting. Perú reports approximately 10-20,000 dengue cases per year, mostly from Loreto and Ucayali. 25% of cases have warning signs and 1% meet WHO criteria for severe dengue [see Image C ].

Gallbladder wall thickening (GWT) is a common finding in dengue. Several patterns of GWT have been reported. A honeycomb pattern is more commonly observed in patients with severe dengue [Ultrasound Int Open 3: E76–E81] while uniform patterns are observed in patients with less severe dengue [Am J Trop Med Hyg 2018; 99:1362].

Treatment of dengue is supportive with hydration and observation for severe sequelae such as DIC, overt plasma leakage and shock. Our patient had abdominal pain – one of the Warning Signs.
 
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

 
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 2019-03

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 2019-03

History: An 18-year-old male, previously healthy, presents with a 5-month history of increasing productive cough, night sweats, watery diarrhea and subsequently low back pain. Epigastric pain, nausea, abdominal distension, episodic watery diarrhea and weight loss began 3 months before admission. Outside treatment for asthma and gastritis was without any improvement. Six weeks prior to admission the patient noticed progressive pain in the right hip and sacral region that irradiated to the right lower limb. The pain became severe and unresponsive to NSAIDs and one week before referral to us was found to be HIV positive at a local emergency department.

Epidemiology: Born and lives in Lima, student. No known TB contacts. He lives with his parents and two siblings, all healthy. He breeds cats, dogs, chicken and guinea pigs at home. No travel history in the past year. No drug use. Sexual history: multiple male partners and sex workers, inconsistent condom use.

Physical Examination: Temp: 40°C; HR: 102: RR: 22; BP: 90/50 mmHg; BMI: 22.8.
Bilateral white plaques on oral mucosa; non-tender left cervical lymph node < 1cm and multiple bilateral small inguinal lymph nodes; crackles in the left apex; liver felt 4 cm below right costal margin. Neurological exam: Limited lumbar flexion, limited hip extension and abduction. Faber Test positive (Flexion, Abduction and External Rotation- Faber Test ), lumbar pain on palpation at L4-S1. No sensory deficit but mild right leg weakness and decreased anal sphincter tone. Bilateral positive Babinski sign. DTR’s positive in lower extremities.

Laboratory: Hb 13.2 g/dl; Hct 39.7%; WBC: 5.44k (N: 89.6 L: 5.6 B: 0.5 E: 0.9)
AST / ALT: 70/42 U/L; Alk Phos: 111mg/dL; Bilirrubin: 0.2
HBsAg negative; HTLV-1/2 negative; CD4+ count: 143 cell/mm3; VDRL negative
Brucella serology: Negative
Chest X ray: normal (Image A).
Lumbar spine X-ray: normal (Image B). MRI of sacroiliac joints (SI) shows inflammation and severe erosion of right SI (Image C, arrow) without new bone formation and inflammation and erosion of vertebral bodies without end plate compromise or disk destruction (Image D, arrows)


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: Extrapulmonary tuberculosis with sacroiliitis and spondylitis
Images for Case 2019-03
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Discussion: A bone marrow biopsy and aspirate from iliac crest showed inflammatory necrosis with histiocytes and lymphocytes without epithelioid differentiation. No evidence of multinucleated giant cells or malignant cells. (Image E) The bone marrow aspirate AFB stain was positive (Image F), and a Gene Xpert MTB-RIF test showed presence of mycobacterial DNA (amplification of IS 6110 and IS 1081) without rifampin resistance (lack of rpoB gene mutations), culture and drug susceptibility testing is pending.

Tuberculosis is caused by 3 related organisms Mycobacterium tuberculosis, M. africanum, and M. bovis. Of these, M. tuberculosis is by far the most common [Reichman LB, Hershfield ES, editors. Tuberculosis: a comprehensive international approach. New York: Marcel Dekker; 1993]. The initial route of entry of M. tuberculosis is usually the respiratory tract, followed by hematogenous dissemination. Secondary hematogenous seeding can occur from a silent focus elsewhere in the body (eg gut, kidney). Skeletal tuberculosis is thought to result from hematogenous dissemination from a primary site and occurs 6 months to 3 years after primary infection; but cases associated with relapsing disease have been reported. Skeletal TB accounts for 10 – 35% of all TB cases with 50% being spinal TB (Pott’s disease). Sacroiliac involvement with radiological abnormalities is uncommon accounting only for 1-5% [J Bone Joint Surg Br. 1997 Jul;79(4):562-6]

In classical TB spondylitis, the disease process begins in a lumbar intervertebral disc and spreads via the anterior ligament to affect the anterior aspects of the adjacent vertebrae. Destruction of the anterior endplates ensues with anterior collapse leading to a wedge deformity. In our patient, there was compromise of the SI joint with spondylitis and multiple vertebral bodies compromise. Interestingly no compromise of endplates (anterior or posterior) were appreciated which could be related to the related immunosuppression due to HIV infection. However, in some series, a high proportion of patients with bony disease had posterior element involvement (28%), all in association with vertebral body disease. [Spinal Tuberculosis in HIV-Prevalent Setting CID 2018:67]. Sacroiliac tuberculosis is often associated with tuberculous lesions elsewhere, and it primarily originates from a tuberculous psoas abscess or tuberculous spondylitis [see Clin Orthop Relat Res. 1999 Jan;(358):215-22]. No psoas abscess was associated in our case, but as seen on MRI (Image E) likely his SI joint involvement originated from the related spondylitis. Given the broad differential diagnosis and the degree of compromise of the SI joint bone marrow aspirate and biopsy were obtained for cultures for mycobacteria but also for other common bacterial pathogens including Brucella and typhoid.

TB sacroiliitis /spondylitis should be differentiated from other infectious disease processes such as pyogenic causes (staphylococcal, gonococcal), typhoid and brucellosis. Non-infectious causes include degenerative and post-traumatic arthritis; inflammatory diseases such as sero-negative spondyloarthropathies, ankylosing spondylitis, psoriatic arthritis, Reiter’s and Behcet’s syndrome, inflammatory bowel disease, rheumatoid arthritis and systemic lupus erythematosus; familial Mediterranean fever with multisystem involvement including arthritis; osteitis condensans ilii; metabolic conditions such as gout pseudogout and hyperparathyroidism; tumors and tumorlike conditions, and pigmented villonodular synovitis [Resnick D, Niwayama G (1995) Osteomyelitis, septic arthritis, and soft tissue infection: organisms. In: Resnick D (ed.) Diagnosis of bone and joint disorders. Saunders, Philadelphia, pp 2461–2485].

Complete destruction of vertebral bodies and the intervertebral disc is seen almost exclusively in infectious processes. Salmonella infection or staphylococcal infections may cause spondylitis and paravertebral abscesses, but concomitant high fever, leukocytosis, and significant systemic illness would be seen. A common feature in these infections is bone remodeling and new bone formation, which was not observed in this patient. Brucellosis, another bacterial cause of sacroiliitis, is endemic in Peru. Spinal brucellosis typically affects the lumbar spine with both lytic and blastic lesions [see Gorgas Case 2001-02]. Malignancy is limited to the vertebral bodies without impinging the intervertebral disc.<

The first and second sacral roots pass near the SI joints, with the joint capsule being bordered by the psoas muscle in front and the gluteal and pyriformis muscles behind. Depending on the capsular region involved in the arthritis, the pain may be gluteal or inguinal, mimicking damage to the hip. Frequently, mycobacterial infections of the sacroiliac joint may present as a psoas abscess, and may not be diagnosed until spontaneous drainage occurs in the groin [see Am J Med. 1988 Mar;84(3 Pt 2):622-8]. Buttock pain is invariably present in tuberculous sacroiliitis (as in our patient). The sacroiliac pain can be referred to the groin, posterior thigh, and occasionally below the knee, mimicking pain originating from the lumbar spine, the hip and the lower abdominal quadrant [see J Bone Joint Surg [Am] 58(6):845–849]. There may be signs of femoral or sciatic nerve root irritation if the distended anterior joint capsule comes in contact with the lumbosacral plexus.

Confirmed diagnosis of TB spondylitis and sacroiliitis in developing countries is difficult, due to limitations in obtaining representative samples and on the low bacterial load associated with these infections. Diagnostic aspiration or biopsy of the sacro-iliac joint is appropriate when there is minimal bone destruction or at early stages of disease. Bone marrow culture and biopsy is extremely helpful as it will help differentiate from other etiologies (ie. brucellosis, typhoid). Molecular methods, such as the Gene Xpert MTB/RIF allow for faster diagnosis and prompt initiation of treatment. Samples such as bone marrow or urine are appropriate and indicate the disseminated nature of the infection [see BMC Infect Dis 2016;16:514].

Treatment of TB sacroilitis is with standard regimens of anti-TB drugs for at least 9 - 12 months, but more prolonged therapy is recommended in patients with extensive bone destruction and vertebral and paravertebral extension. In TB sacroiliitis, controversy exists as to the need for early surgery. In some series, healing of the infection was accelerated when debridement was done prior to treatment initiation. None of the studies of shorter course chemotherapy have included enough patients with skeletal disease to make any conclusions possible. Patients with acute neurologic deficits within the previous 12-24 hours that suggest extension of disease into the spinal canal should definitely have surgery. Steroids should be considered for very severe paraplegia, especially in the acute stage. Recommendations for a surgical procedure in TB spondylitis include (1)Patients with spinal disease and advanced neurological deficits, (2)Patients with spinal disease and worsening neurological deficits progressing while on appropriate therapy, (3)Patients with spinal disease and kyphosis >40 degrees at the time of presentation and (4)Patients with a cold abscess in the chest wall.

Our patient was started on the standard 4-drug initiation regimen of daily isoniazide, rifampin, ethambutol, and pyrazinamide in addition to prednisone for the neurological compromise. Surgical evaluation and discussion of approaches to further joint stabilization are ongoing. ARV treatment was initiated with EFV/TDF/FTC.

 
University of Alabama at Birmingham

Gorgas Case 2019-04

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 2019-04

History: A 47-year-old male, HIV positive, presents with a 6-month history of abdominal pain, watery diarrhea, fever and weight loss.

HIV was diagnosed in 2017 with irregular treatment. Current ART regimen: tenofovir/emtricitabine/efavirenz. Patient now presents with 6 months of an insidious course of fever and abdominal pain progressing to episodic and profuse watery diarrhea. At a local clinic, the patient is clinically diagnosed with intestinal tuberculosis based on clinical criteria and initiates treatment with standard TB therapy four months before admission. However, symptoms persisted and 1 month before admission progressive dysphagia, productive cough and sporadic hemoptysis ensues.

Epidemiology: Born in Chiclayo, resides in Jaen, Cajamarca but has been living in Lima for 8 months.

Physical examination: T 36.7°C HR 120 RR 24 BP 90/50 Sat: 98 % (FiO2: 0.21)
Acutely ill, somnolent with marked pallor of the mucous membranes. No skin lesions. No lymphadenopathy. Few inspiratory rales were heard in both lungs. Normal heart sounds, no murmurs. RUQ and epigastric tenderness, hepatic span of 15cm, the tip of the spleen was felt.

Laboratory result at admission: Hb: 7.7g/dL; WBC 1500 (0%bands, 87% neutrophils, 2% eosinophils, 8.5% lymphs); Platelets: 150 000; INR 2.35; Glucose 96 mg/dl; urea 33 mg/dl; creatinine 0.8 mg/dl; total bilirubin: 0.7 mg/dl; ALT 18 U/L (N=< 40); AST 78 U/L (N=<40); Alk phosphatase 406 mg/dl (N 15-60); GGT 400. LDH 1106. CD4 222; VL 361000. Negative tests for O & P including search for Strongyloides, Giardia and coccidian parasites, stool culture negative for bacteria. Negative Ziehl-Neelsen in a sputum sample as well as negative Gene Xpert MTB/RIF.

The chest x-ray showed bilateral interstitial infiltrates that were corroborated in the chest CT-scan [Image A]. An abdominal CT-scan showed visceromegaly [Image B]. A colonoscopy was performed, multiple colonic ulcers were observed scattered over the entire colon and ileum [Image C].


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: Progressive disseminated histoplasmosis (PDH) due to Histoplasma capsulatum
Images for Case 2019-04
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Discussion: A biopsy of a colonic ulcer showed a dense histiocytic infiltrate within the lamina propia. [Image D]. Multiple oval-shape intracellular structures measuring 3-4 microns compatible with H. capsulatum were identified in a Periodic Acid Schiff stain [Image E] and in a Grocott stain [Image F]. The differential diagnosis includes paracoccidioidomycosis where the yeast cells would be of different sizes and show multiple peripheral budding mimicking a pilot´s wheel, and visceral leishmaniasis; not endemic in Peru, you would expect to see a kinetoplast. Definitive diagnosis in these cases is made by fungal (bone marrow, blood or tissue culture lymph nodes, skin or oral lesions) as a gold standard, these results are pending. Cultures are positive in about 75% of patients [AJTMH 2013;89:937]. Urinary Histoplasma antigen is very useful (97% sensitivity) but usually not available in developing countries [PLoS Negl Trop Dis 2018;12(10):e0006802]. Direct observation of yeast cells from blood samples has low sensitivity (10%), better results are obtained from bone marrow samples.

H. capsulatum is a dimorphic endemic fungus of worldwide distribution but is most common in North America and Latin America. In highly endemic areas more than 80% of persons are infected by age 20, often sub-clinically. Bats, which often live in caves, are frequently infected. Acquisition is inhalational with principal sites of disease in lungs, lymph nodes, liver, spleen, bone marrow, adrenals and the GI tract. Histoplasmosis is endemic in Latin America including Peru, the fungus is predominantly found in jungle areas. The reported incidence among advanced HIV-infected patients varies from 8% in Panama to 42% in French Guyana, being the first or second opportunist infection in these patients [AIDS 2016;30:167]. A necropsy study of 16 patients who died with advanced AIDS in Lima, Peru found that 3 (19%) had disseminated histoplasmosis [Pathol Res Pract 2006;202:767]. Exogenous acquisition or reactivation of a latent foci, as in this case are the modes of acquisition.

Histoplasmosis is the most common endemic mycosis among HIV-infected patients. Progressive disseminated histoplasmosis (PDH) as demonstrated by this patient is the most common manifestation of histoplasmosis in AIDS patients. PDH may be the first manifestation of advanced AIDS in endemic areas, a study among 89 patients with advanced AIDS in Colombia found 45 (51%) with PDH [AJTMH 2016;95:918]. Predictors of PDH were significant weight loss, hepato or splenomegaly, skin lesions and hematologic abnormalities (mainly pancytopenia), many of them seen in this patient. Pulmonary involvement is seen in about 50-70% with non-specific manifestations (dry cough, chest pain, dyspnea); 50-70% of patients have abnormal radiologic findings; diffuse interstitial infiltrates or reticulonodular infiltrates are the most common abnormal findings. PDH is associated with high mortality rates, a study among 101 confirmed cases in Guatemala found a crude mortality rate of 44% with a median survival time of 19 days [AJTMH 2017,97:42]; a Peruvian case series from a single center found that 59% (16) of 27 HIV-infected patients with histoplasmosis had PDH, with a mortality rate of 22% [Rev Chilena Infectol 2017;34:365-9].

Chronic diarrhea is a common clinical presentation among HIV-infected patients. A long list of potential causes includes bacteria, viruses, parasites, fungi and malignancies. A study conducted in Peru among 147 HIV-infected patients showed that Cryptosporidium sp. Giardia lamblia and bacterial agents were the most common etiologies of persistent-chronic diarrhea [J Infect Dis 2005;191(1):11, PMID 15592997]. Intestinal histoplasmosis has been reported among patients with advanced HIV-infection. Chronic diarrhea, wasting, vomiting, gastrointestinal bleeding, altered bowel habits and intestinal obstruction have been reported, multiple colonic ulcers are commonly observed [Int J Surg Pathol 2017;25(7):592]. Due to the non-specific nature of PDH presentation, patients with chronic diarrhea in endemic areas should be investigated for histoplasmosis.

USA treatment guidelines [Clin Infect Dis 2007;45:807] recommend induction therapy with liposomal amphotericin B (or amphotericin B deoxycholate in persons with low risk for nephrotoxicity) for 1-2 weeks followed by itraconazole for at least 1 year, with dosing guided by measurement of serum drug levels. Suppressive therapy with itraconazole is stopped if patients have received one year of itraconazole therapy, have negative blood cultures, low levels of urinary antigen (<2ng/ml), a CD4 cell count >150 cells/mm3, and patients are on HAART. Initiation of HAART should not be delayed; IRIS is rare and usually not severe.

Our patient had been started empirically on anti TB treatment with standard 4-drug therapy, which will not be continued, as there was no evidence of such an infection, and is currently receiving amphotericin deoxycholate. He will be started on ART after 2 weeks of induction therapy with amphotericin B. Failing a non-nucleoside reverse transcriptase reverse inhibitor-based regimen due to inconsistent adherence in developing countries compromises the selection of second-line regimens, a boosted protease inhibitor-based regimen will be selected in this patient [Lancet HIV 2017;4(10):e433].

 
University of Alabama at Birmingham

Gorgas Case 2019-05

Universidad Peruana Cayetano Heredia
During Week 5 of the course, the annual field trip to Cusco in the Andean highlands took place. Cusco (elevation 3400m) is the oldest continuously inhabited city in the Americas. The patient was seen in the Hospital Antonio Lorena in Cusco. We thank Dr. Fatima Concha for presenting the case to the class.
Image for Case 2019-05

History: A 47-year-old female patient presented to the Antonio Lorena Hospital in Cuzco city with a 2-month history of progressive abdominal pain. The patient describes initial mild, colicky, right upper quadrant pain with no irradiation. After an initial response to analgesics, the pain worsened and one week before admission when she noticed more severe pain and nausea and vomiting. She denies fevers, anorexia, weight loss or other constitutional symptoms, no respiratory symptoms.

Epidemiology: Born in the Andean highlands of Apurimac but lives in Cuzco city. Housewife. Owns dogs and guinea pigs at home. No travel history. No history of trauma.

Physical examination: T 36.5 C, HR 75, RR 24, BP 100/60, Sat 94% (FiO2: 021)
No skin lesions, no lymphadenopathy, normal chest and cardiovascular examination. Painful hepatomegaly palpated 3 cm below the right costal margin, no splenomegaly.

Laboratory result at admission: Hemoglobin 11g/dl; WBC 8730 (21% eosinophils); INR 1.43; platelets 405,000; glucose 97 mg/dl; normal liver function tests; negative stools for ova and parasites
Abdominal ultrasound showed hepatomegaly (13cm) and the presence of a heterogeneous sub-capsular fluid collection of 150x150 mm in the antero lateral border of the liver [Image A]. An abdominal CT-Scan of the abdomen showed a hypodense subcapsular collection of approximately 500cc (red arrow) and multiple small hypodense lesions in the liver (black arrow), the gallbladder and pancreas look normal, no dilatation of the common bile duct [Image B]


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: Subcapsular liver hematoma due to Fasciola hepatica infection (acute phase)
Images for Case 2019-05
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Discussion: IgG Fas2 ELISA was positive for Fasciola hepatica. Eggs of F. hepatica were observed in stool samples [Image C]. On further questioning, the patient admitted frequent consumption of lettuce and raw watercress.

Fasciola hepatica is a trematode (fluke or flatworm) in which the mature adult parasites inhabit the large biliary ducts. As with all other trematodes, Fasciola hepatica requires a snail intermediate host. Eggs produced by the hermaphroditic adults pass with the feces and hatch, releasing larvae in fresh water. After passing through a snail, mature cercariae emerge and rapidly encyst on various kinds of aquatic vegetation such as watercress. After ingestion by a human or animal definitive host, the metacercariae excyst in the duodenum and larvae penetrate the intestinal wall and subsequently directly into the liver via Glisson’s capsule embarking on a destructive migratory process through the hepatic parenchyma for 3-4 months until they reach large biliary ducts where they mature to adults. As in this case, migration through a capsular vessel may result in significant hemorrhage. The mature adults are from 1-3 cm long and attach to the biliary epithelium by a single ventral sucker. In the absence of direct visualization of adults, characteristic eggs can be seen on stool examination, but more often patients present in the early migratory phases of infection prior to maturation of the worm and the onset of egg-laying. Specific serology is the test of choice but lacks sensitivity. More modern methods including PCR amplification have shown higher sensitivity and specificity than the current standard [Am J Trop Med Hyg 2017;96(2):341].

The distribution of Fasciola hepatica is cosmopolitan, but is by far the most common in sheep-raising areas where herbivores are common definitive hosts [Curr Opin Infect Dis 2018;31(5):409]. Heavily infected sheep develop “sheep liver rot”. Other important definitive hosts are goats, cattle, horses, llamas, vicunas, and camels. The contiguous Altiplano regions of the Peruvian and Bolivian Andes are highly endemic, with human prevalence rates of as high as 67% in some villages. Egypt, Cuba, and Northern Iran are also highly endemic and the parasite is emerging in Vietnam and Cambodia. Cooking, which would kill the metacercariae, dramatically changes the flavor of watercress and the population is reluctant to adopt this simple measure.

Clinically, the disease can be divided into acute and chronic phases. During the acute phase, migrating parenchymal larvae generally cause fever, eosinophilia, right upper quadrant pain and especially significant anorexia. Vomiting and weight loss of 20 kg or more may develop, which usually abates when the larvae mature to adults. The adult flukes in the biliary tree are generally asymptomatic but some patients develop chronic manifestations including right upper quadrant pain, nausea, vomiting, and hepatomegaly. Eosinophilia and abnormal liver function may develop but are less common than with acute disease. Adult flukes may cause hyperplasia, desquamation, thickening, and dilatation of the bile ducts. We have reported a case series with clinical findings and evolution of disease [Am J Trop Med Hyg. 2008;78:222-7]. Please see Gorgas Case 2005-02 for a CT image of the typical larval tracks seen in acute disease and as well direct visualization of adult flukes via ERCP.

The differential diagnosis of eosinophilia with accompanying destructive hepatic lesions is limited. Toxocariasis causes hypereosinophilia with hepatomegaly but the pathology results from small granulomas around individual non-migrating larvae and not the large destructive lesions seen in our patient. Eosinophilia is common in Perú so it may be due to an unrelated event present concomitantly with a bacterial liver abscess; this had been the initial impression in this case.

Subcapsular liver hematoma is a rare complication of acute fascioliasis. Very few cases have been reported in the medical literature [Am J Trop Med Hyg 2019;100(3):588; Clin Infect Dis 2011;52(9):1137; Rev Gastroenterol Peru 2003;23(2):142]. While most of these cases required only medical treatment and careful clinical observation with regular hemoglobin measurements, some patients developed hemodynamic instability and required surgical intervention.

Fasciola hepatica is the only trematode infection for which praziquantel is not the drug of choice. WHO has put the anthelmintic triclabendazole (Egaten, Novartis) on its essential drugs list. Egaten is registered in Perú (as in Mexico and Egypt) and is available via free donation from the WHO. Egaten has been recently approved by the US FDA and will be available free of charge in the USA. The usual dosage is 10mg/kg with a meal. Many practitioners repeat the dosage 12-24 hours later.

Our patient was treated with a two-day regimen of 10 mg/kg/day of triclabendazole. The hemoglobin dropped to 7.8 g/dl over a period of one week of observation but no hemodynamic instability occurred. Interestingly, stool samples were positive for eggs [Image C] after 3 months of therapy and remained positive after two additional cycles of triclabendazole in absence of subsequent exposure. Failure to eliminate eggs of F. hepatica after repeated cycles of triclabendazole has been reported in Cuzco [PLoS Negl Trop Dis 2016;10(1):e0004361]. No consensus on how to treat these patients does exist, higher doses of triclabendazole for 2 days are recommended.

 
University of Alabama at Birmingham

Gorgas Case 2019-06

Universidad Peruana Cayetano Heredia
The following patient was seen in the inpatient department of pediatrics at Cuzco’s Regional Hospital. We would like to thank Dr. Felix Hidalgo, Director of the Hospital for his contribution in presenting this case.
Image for Case 2019-06
History: 12-yo female presenting with a 3-month history of malaise, fever, diarrhea and generalized lymphadenopathy. Three months before admission, the patient developed loss of appetite and nausea, followed by 3 to 4 daily episodes of watery diarrhea and diffuse abdominal pain. During this period, the patient’s mother noted the presence of several cervical nodules and persistent fever. Symptoms progressed to include bloody diarrhea and a 10 kg weight loss. She was then referred to the Regional Hospital.

Epidemiology: Born and raised in Kiteni, Concepcion (jungle of Cuzco region). She is a student. No recent travel history. No known TB contacts. Two years earlier she had been admitted to our hospital due to a similar clinical presentation.

Physical examination: T 37.7C; HR 90; RR 22; Sat O2 94 %
Pallor +++. Multiple enlarged lymph nodes ranging from 0.5 to 2 cm in diameter in cervical, retroauricular, submandibular, axillary, inguinal and umbilical regions. Chest: clear to auscultation Abdomen is distended. The liver is 2 cm below the costal margin, the spleen is felt crossing the midline. Rest of the physical examination is unremarkable.

Laboratory result at admission: Hb 7.3 g/dl; WBC 7020 (N 72% L 12% M 4% E 13%); platelets: 166,000; glucose: 70 mg/dl; albumin: 3.2 g/dl; total bilirubin 1.5 mg/dl; alkaline phosphatase 221; ALT 7 IU/l, creatinine 0.62 mg/dl. HIV, Syphilis, HBsAg: negative. HTLV-1 pending. Stool culture for bacteria and tool examination for ova and parasites: negative
Chest x-ray: no pulmonary infiltrates, no pleural effusion. Abdominal CT-scan [Image A,B].

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

Diagnosis: Paracoccidioidomycosis, juvenile form
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Discussion:
Cervical lymph node biopsy showed that the normal architecture of the lymph node was distorted. The cortex was infiltrated by granulomatous lesions composed of epithelioid cells and multinucleated giant cells containing phagocytosed spherical structures of variable size (5-30um) [Image C], some of them show multiple peripheral budding mimicking a “pilot wheel” suggestive of yeast cells of Paracoccidioides braziliensis [Image D]. If skin lesion were present direct scrapings or aspirates will be positive in the vast majority of cases. Official reading of the CT scan disclosed hepatomegaly with no focal lesions, splenomegaly with no focal lesions diffuse intra-abdominal lymphadenopathy, and no other mass lesions.

Records from prior admission 2 years earlier disclosed a similar episode of malaise, fever and subcutaneous nodules. During this episode, she was diagnosed with juvenile paracoccidioidomycosis (PCM). She was treated with amphotericin B and upon discharge was switched to oral itraconazole. Due to economic constraints the family was not able to complete the therapy and stopped it after 5 months without communicating with medical officers.

Paracoccidioidomycosis, previously known as South American Blastomycosis, is a systemic fungal disorder endemic in rural areas of Latin America that is acquired through the respiratory route with the lungs constituting the primary target while all other organs (lymph nodes, mucous membranes, skin, adrenals, bone, other) represent secondary manifestations. PCM simultaneously involves more than one organ or system and, as such, should be considered a systemic disorder.

PCM is most frequently reported in Brazil, Venezuela, Colombia, Peru and Argentina. It is caused by thermally dimorphic fungi nested within the genus Paracoccidioides (Curr Fungal Infect Rep (2012) 6: 303Curr Fungal Infect Rep. 2012 Mar; 6(1): 23–34) Recently, molecular tools allowed to revise the taxonomy of this genus determining two species, P. brasiliensis and P. lutzii. Moreover, genetic analysis revealed that P. brasiliensis is not a single species but rather a species complex comprising at least four genetic entities: S1, PS2, PS3, and PS4. However, the clinical impact of this genotypic diversity, if any, has not yet been investigated. (Future Microbiol. 2013 Sep;8(9):1177-91)

The infection is usually acquired in the first two decades of life, and it is commonly subclinical, although the fungus can also cause chronic and severe diseases. Most often it is an indolent and relapsing disease causing chronic pulmonary and mucosal manifestations. It is estimated that 10 million people are infected with Paracoccidioides spp. in Latin America, of whom only about 1–2% will develop PCM.(Med Mycol. 2011 Nov;49(8):785-98)

PCM predominantly afflicts adult males involved in agriculture and it has a particular gender distribution with a predilection for adult males at a ratio of ≥11 to 1. The disease has mostly a chronic profile with acute/subacute forms accounting for less than 15% of all reports. PCM is uncommon in children and adolescents and the acute/subacute clinical form as seen here is commonest in children and adolescents and represents only 3–5% of all cases. Despite the low incidence, potentially life-threatening and mortality rates may be high. (PLoS Negl Trop Dis. 2017 Mar 29;11(3):e0005500)

The chronic form (adult type) of the disease is believed to represent reactivation of latent infection initially acquired via inhalation. The chronic forms represent approximately 94% of all cases in the experience at our institute (100 patients), and approximately 85% in the Brazilian series (Rev Soc Bras Med Trop. 2003 Jul-Aug;36(4):455-9). See examples of this in Gorgas Cases 2005-12, 2009-06, and 2004-05]. We have also previously shown a case of the chronic progressive form of the disease [Gorgas Case 2003-07].

After an initial inhalation event (Clin Infect Dis. 2005 Jan 1;40(1):148-57) which is usually self-resolving, the acute juvenile type systemic disease of PCM may progress from the primary focus of infection without a latency period. Once the disease is established, the patient may develop an acute or sub-acute pattern of clinical manifestations and a rapid clinical deterioration. In a few months or weeks, an acute and febrile rapid course with weight loss and multi-organ compromise is usually observed.

As a consequence of the tropism of Paracoccidioides to the monocyte-phagocyte system, a marked involvement of the reticuloendothelial system characterizes this clinical form, (Med Mycol. 2013 Apr;51(3):313-8) and diffuse lymphadenopathy, hepatosplenomegaly, and papular skin lesions with a large burden of yeast forms are usual clinical manifestations as in this patient. Anemia, hypergammaglobulinemia, and eosinophilia are additional manifestations. Poor nutrition may compromise cellular immunity and has been considered an important predisposing condition to developing PCM, especially in younger adults with extensive abdominal lymphadenopathy. (Mycopathologia. 2006 Feb;161(2):73-81) As is typical in acute cases, in our case no pulmonary compromise was observed, but there was mucosal compromise in the colon (figure D), associated with bloody diarrhea. Our patient presented anemia related to the disease itself but also aggravated by gastrointestinal losses due to colonic mucosa compromise. The finding of an O2 Sat of 94% is considered normal when at high altitude, Cusco is at 3200 mt above sea level.

A cardinal presentation in our patient was massive splenomegaly on presentation. The differential diagnosis of severe hypersplenism (massive splenomegaly) would include visceral leishmaniasis (not present in Perú, but present in Brazil, Venezuela and Colombia), schistosomiasis (not present in Perú, but present in Brazil, Surinam and Venezuela), chronic brucellosis, hematologic malignancies, and hemophagocytic syndromes. Hyper-reactive malarial splenomegaly syndrome (HMSS) represents one of the leading causes of massive splenomegaly in malaria-endemic countries (Lancet. 2002 Aug 10;360(9331):449-54). Other causes of severe and potentially massive splenomegaly include EBV infection, infective endocarditis, and mycobacterial infections. Disseminated histoplasmosis does not usually cause as massive splenomegaly.

Sulfonamides, ketoconazole, itraconazole, and amphotericin B are all effective therapies. Amphotericin B induction therapy for 2 – 4 weeks should be reserved for severe cases or relapses such as this one prior to initiation of itraconazole. For milder cases, itraconazole 100-200 mg/day is the treatment of choice without Amphotericin B induction. A total length of therapy of no less than one year is regarded as the treatment of choice for both the juvenile and chronic forms when it is available and affordable. In resource constraint settings ketoconazole and TMP/SMX become attractive alternatives at a fraction of the cost although in those cases expert opinion will favor at least 12 months of therapy.

In this severe and relapsing case, the plan is to give amphotericin B for one month, follow by at least one-year with itraconazole or TMP/SMX. In some instances, lifelong suppressive treatment is a consideration.
 
University of Alabama at Birmingham

Gorgas Case 2019-07

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. We would like to thank Dr. Dalila Martinez for her contribution in preparing this case for presentation.
Image for Case 2019-07
History: A 63-year-old, previously healthy, male patient is admitted with an 8-month history of an indurated erythematous plaque affecting the nose and left maxillary region, rhinorrhea and headache. The patient first reports serous rhinorrhea and nasal congestion eight months prior to admission. Six months prior to admission, he noted an erythematous plaque that began in the left maxillary region. Over the ensuing weeks to months, the plaque progressed despite several rounds of antibiotic therapy and eventually compromised the nose. Due to symptom persistence, the progression of the plaque, the development of nighttime fevers and headaches, the patient was referred to our institution for further evaluation.

Epidemiology: Born and lives in Hualmaca, Chiclayo; a rural area in the northern coast of Peru. Works as a farmer. Frequent contact with cats, dogs, chicken and cattle. Recurrent exposure to fresh-water ponds and rivers. No history of nor exposure to TB. No recent travel history.

Physical examination: Temp: 36.5 °C; HR: 62: RR: 18; BP: 125/76 mmHg; weight: 66.8 kg; O2 Saturation: 97%
A 7x8 cm infiltrated violaceous plaque with well-defined edges that involves the nose and left maxillary region. There is edema and erythema of the left nares and nasal mucosa [Image A, panels a and b]. No other lesions, discharge or abnormal findings in the oropharynx. Glasgow score of 15, no focal neurologic deficits nor signs of meningeal irritation are found. Muscle strength is preserved symmetrically, bilaterally. The rest of the physical examination is unremarkable.

Laboratory result at admission: Hb 10.6 g/dl; MCV: 92; MCH: 30.3; MCHC: 32.8; WBC: 3.4k (N: 61.9 L: 27.8 B: 1 E: 3.6); platelets: 182 000; glucose: 118 mg/dl; urea: 15.4 mg/dl; creatinine: 0.8 mg/dl ; HIV: negative; VDRL: negative.

MRI of the brain: three lesions with diffuse enhancing in the T1-weighted sequence with gadolinium were observed, one in the right frontal lobe and one in the right temporal lobe, and another one in the left occipital lobe [Image B, panel a]. The same lesions looked bright in the FLAIR sequence [Image B, panel b].

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

Diagnosis: Balamuthia mandrillaris (free-living amoeba)
Images for Case 2019-07
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Discussion:
 A skin biopsy [Image C] revealed the presence of a lymphoplasmacytic and histiocytic inflammatory infiltrate of moderate intensity with poorly formed granulomas and evidence of multinucleated giant cells. Two structures compatible with amoebic trophozoites were observed. Based on our clinical experience with more than 50 cases and the characteristic skin and brain lesions occurring in concert, a diagnosis of Balamuthia mandrillaris was made. See cases 2007-10, 2004-2, 2015-6 for other patients with these same characteristic manifestations of B. mandrillaris infection.

About 200 cases of B. mandrillaris infection have been reported worldwide. Disease has been reported from all continents except Africa. Most cases are reported in the Western hemisphere, with the highest concentration in South America and the United States of America. The disease appears to occur more frequently among patients of Hispanic origin. Possible explanations include genetic susceptibility or high environmental exposure. As in most Latin American cases, our patient was not immunocompromised.  Unlike Acanthamoeba and Naegleria species, which are more familiar to clinicians and known to occur in brackish ponds and creeks, an ecologic niche in nature has not been definitively found for Balamuthia. Entry of water into the nasal mucosa and the olfactory nerve endings is thought to precede Naegleria infection. Our patients with Balamuthia infection have come from throughout Peru with most coming from desert areas and not always reporting a history of swimming in potentially contaminated fresh water. Naegleria infection causes an acute necrotizing and suppurative meningoencephalitis, an aggressive disease that is generally fatal in days. Acanthamoeba cause a sub-acute granulomatous encephalitis with a more prolonged but ultimately fatal course mainly seen in immunocompromised hosts. Occasionally, patients with Acanthamoeba may develop a chronic cutaneous ulcer. Acanthamoeba, unlike Balamuthia, has also been associated with amoebic keratitis, a painful sight-threatening disease of the eye which may be associated with contact lens use.

In Balamuthia infection, the disease may follow also a prolonged course with an ultimately fatal outcome. Almost all cases have an initial skin lesion preceding CNS disease (granulomatous amebic encephalitis) by weeks or months. The CNS lesions generally appear distant or as metastases from the primary cutaneous lesion. Sometimes as in this case, there may be several metastatic lesions in different parts of the brain and one may seem to be due to direct local extension from the skin lesion [Image B]. Infected patients range from 3 to 65 years of age with 50% under age 15. The typical skin lesion is a single painless plaque up to several centimeters in diameter; a few patients have had 2-3 lesions. Color may be skin tone, dark red, or slightly violaceous. Sensation is preserved. Location is usually on the central face with fewer than 10% with lesions on trunk or extremities. For facial lesions, the differential diagnosis may include tuberculosis, mucocutaneous leishmaniasis, sporotrichosis, leprosy, paracoccidioidomycosis, rhinoscleroma, or atypical mycobacteria. Sarcoid, discoid lupus, cutaneous lymphoma (NK lymphoma) and Wegener’s can also be considered. Histologically, granulomatous inflammation with lymphocytes, histiocytes, plasma cells, as well as giant cells, is characteristic. Amoebic trophozoites are often rare and multiple sections need to be examined for their detection. Some foci of vasculitis may be present as well.

Balamuthia
CNS involvement most often manifests with headache, photophobia, seizures that progress to lethargy, sensori-motor deficit(s), coma and death. CNS lesions undergo progressive hemorrhagic necrosis with large numbers of amoebic trophozoites and cysts invading vascular structures (sub-adventitial areas of arteries, veins, and capillaries), leading to perivasculitis and cerebral infarcts [Hum Pathol. 1999 Mar;30(3):269-73].

The mainstay of successful treatment for Balamuthia depends on early diagnosis and therapy. Patients without brain lesion(s) at diagnosis have better chances of recovery. Treatment with drug combinations for prolonged periods is warranted. This patient was started on fluconazole, albendazole, and miltefosine based on our prior experience with one patient [Clin Infect Dis. 2010;51(2):e7-11]. Our center has treated 12 patients with and without CNS involvement since that publication with this three-drug combination, 7 survived with complete clearance of the lesions [Martínez DY. Personal communication]. This drug regimen is well tolerated and the most important side effects are nausea, stomach ache, and vomiting. Treatment ranged from 6 to 18 months in most of these cases.

Miltefosine crosses the blood-brain barrier and is known to have an in-vitro amebicide effect against B. mandrillaris [J Eukaryot Microbiol. 2006 Mar-Apr;53(2):121-6]. Although formal trials are lacking a number of case reports have shown good results when using miltefosine as part of a combination of drugs to treat free-living amebic infections including Naegleria sp. Acanthamoeba and B. mandrillaris. Miltefosine is FDA-approved and available in the US but therapy is costly and there is a single manufacturer. Fluconazole produces an amebistatic effect by interfering with ergosterol metabolism (ergosterol is one of the main components of the amebic wall). Albendazole affects cell motility, maintenance of cell shape, intracellular transport and diminishes ATP production. Both drugs, have good CNS penetration.

Other drugs with amebicidal effects are: pentamidine and some antipsychotic agents (phenothiazines and thioridazine). Unfortunately, they are poorly tolerated. While IV amphotericin B or pentamidine, have produced initial, apparently favorable responses including disappearance of cutaneous lesions, their administration still does not halt the eventual appearance of CNS disease. Similarly, in our experience, multi-drug combination therapy with agents such as albendazole, itraconazole, or fluconazole without miltefosine do not halt the eventual appearance of or progression to CNS disease.