Gorgas Case of the Week - 2017 Series

University of Alabama at Birmingham

Gorgas Case 2017-10

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. Each August we conduct one of our 2-week refresher courses for those with previous training in tropical medicine; currently in session is the Gorgas Advanced Course. For the past 16 years, we have been pleased to share interesting cases seen by the participants each week when our courses are in session; there will be one more case next week to complete the 2017 case series.

The following patient was seen in the Intensive Care Unit of the Children’s Hospital in Lima, Perú.

Eduardo Gotuzzo & German Henostroza
Course Directors
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History: An eight-year-old male patient, previously healthy, admitted with a two-month history of a painless, progressive, violaceous plaque on the left side of the nose, which was unresponsive to 10 days of antibiotics. Ten days before admission weakness of the left arm was followed by weakness in both lower extremities then both upper extremities as well as onset of rhinorrhea. Frontal and occipital headache, nausea, vomiting, began 1 week prior to admission. Progressive difficulty swallowing, somnolence, and altered mental status led to hospital admission and subsequent transfer to our hospital.

Previously healthy child, fully vaccinated. Trauma to the nose in the weeks prior included bumping into a wooden column, being hit with a plastic and being kicked in the nose (with no bleeding but with swelling that resolved spontaneously).

Epidemiology: Born and lives in Piura, north coastal desert of Peru. Contact with cats, dogs and chicken. No history of fresh-water exposure in lakes, ponds or rivers. No known TB contact. No relevant family history. Travel to a rural valley two weeks before admission for 15 days for treatment by a traditional healer.

Physical Examination: Febrile. Blood pressure: 140/90. Heart rate: 140. Respiratory rate: 60, O2 saturation: 89%. In obvious distress. Skin: Infiltrated violaceous plaque, with superficial desquamation, with defined edges in the left lateral region of the nose (Image A). No other lesions, discharge or abnormal findings in the oropharynx. Neurological exam, stuporous with a Glasgow coma scale of 10 (AO: 4 RV: 2 RM:4), hyper-reflexia and nuchal rigidity positive, but other meningeal signs negative, Babinski negative, normal ocular movements. No lymphadenopathy. The rest of the exam was normal.

Laboratory: Hematocrit: 36%, hemoglobin: 11.1 g/dL, platelets: 543,000. WBC 14,900 (85% neutrophils and 0.8% eosinophils); normal liver function tests, glucose, creatinine, urea, and electrolytes. CT scan is shown (Image B).

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator / Karen  Luhmann, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Balamuthia mandrillaris (free-living amoeba).
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Discussion: A skin biopsy (Image C) revealed a flattened epidermis and diffuse infiltration of the reticular dermis by a lymphoplasmacytic infiltrate and multiple randomly distributed multinucleated giant cells. Some structures are observed inside apparent vacuoles that present a cytoplasm with bubbles and nuclei and nucleoli. The CT was read as severe edema, predominantly of the right hemisphere, multiple hypodense lesions, the largest located on the right of the midline with ring enhancement causing ventricular collapse and midline deviation. Based on our clinical experience with over 50 cases and the characteristic skin and brain lesions 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 this infection.

About 200 cases of B. Mandrillaris infection have been reported from all continents except from Africa. Most cases are reported in the western hemisphere, with the highest concentration in South America and the United States. The disease appears to occur more frequently among patients of Hispanic origin; possible explanations include genetic susceptibility or environmental exposure. Like most Latin American cases, the patient is 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. Our patients have come from throughout Peru, usually from desert areas and not always reporting a history of swimming in potentially contaminated fresh water. Entry of water into the nasal mucosa and the olfactory nerve endings is thought to occur with Acanthamoeba and Naegleria.

Naegleria infection causes an acute necrotizing and suppurative meningoencephalitis, an aggressive disease that is generally fatal in days. Acanthamoeba cause a sub-acute granulomatis encephalitis with a more prolonged but ultimately fatal course mainly seen in immunocompromised hosts. Occasionally, patients with Acanthamoeba have a skin lesion usually described as a chronic ulcer. Acanthamoeba, unlike Balamuthia, has been associated also with amoebic keratitis, a painful sight-threatening disease of the eye. In Balamuthia infection, the disease may follow a prolonged course, but most frequently has a fatal outcome. Almost all cases have an initial skin lesion, and this lesion precedes the inevitable CNS disease (granulomatous amebic encephalitis) by weeks or months. The CNS lesions generally appear distant or as metastases from the primary cutaneous lesion but uncommonly as in this there may be direct local extension to the brain. Patients have ranged 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 initial lesions on trunk or extremities. For facial lesions, the differential diagnosis may include tuberculosis, mucocutaneous leishmaniasis, leprosy, sporotrichosis, paracoccidioidomycosis, rhinoscleroma, or mucormycosis. Sarcoid, discoid lupus, and Wegeners can also be considered. Histologically, granulomatous inflammation with lymphocytes, histiocytes, plasma cells, as well as giant cells, is characteristic. Amoebic trophozoites are often scanty and multiple sections need to be examined. Some foci of vasculitis may be present.

CNS involvement most often manifests with headache, photophobia, seizures that progress to lethargy, sensori-motor deficit, coma and death. The CNS lesion is a progressive hemorrhagic necrosis with large numbers of amoebic trophozoites and cysts invading vascular 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 depends on early diagnosis and therapy. Patients without brain lesion 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 experience with one patient [Clin Infect Dis. 2010;51(2):e7-11]. Our center has treated 11 patients with CNS involvement since that publication with the three drug combination, 7 survived with complete clearance of the lesions. This drug regimen is well tolerated; the most important side effects are nausea, stomach ache, and vomiting. The duration of treatment in most of these cases was from 6 to 18 months.

Miltefosine is known to have an in-vitro amebicidal effect against B. mandrillaris [J Eukaryot Microbiol. 2006 Mar-Apr;53(2):121-6] and crosses the blood-brain barrier. 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 affections, including Naegleria sp. Acanthamoeba and B. mandrillaris and in the US miltefosine is FDA-approved and available but costly from a single commercial distributor. Albendazole and fluconazole are amebistatic effect; they interfere with the metabolism of ergosterol, one of the main components of the ameba wall. Fluconazole has good CNS penetration.

Other drugs with amebicidal effect are: pentamidine, antipsychotic agents’ phenothiazines and thioridazine. However, they are poorly tolerated. With IV amphotericin B or pentamidine, an initial and apparently favorable response or disappearance of cutaneous lesions still does not halt the eventual appearance of CNS disease. Similarly, in our hands, multi-drug combination therapy with agents such as albendazole, itraconazole, or fluconazole without miltefosine have still resulted in eventual appearance or progression of CNS disease.

University of Alabama at Birmingham

Gorgas Case 2017-09

Universidad Peruana Cayetano Heredia
The following patient was seen in the outpatient clinic of the Tropical Medicine Institute in Lima, Perú.
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History: 44-year old male presented to the outpatient clinic with palpitations and dizziness. An arrhythmia had been diagnosed 5 years earlier but he reported being completely asymptomatic until the past month. He has noted daily palpitations and two episodes of dyspnea on exertion associated with dizziness that resolves with rest. He denies fevers, chest pain, syncope, and dyspnea at rest, orthopnea, nocturnal paroxysmal dyspnea or lower extremity edema. No gastrointestinal complaints. No history of hypertension or diabetes. No antecedent flu-like illnesses. He underwent surgery for kidney stones 10 years ago.

Epidemiology:Born and lived in Cajamarca and in the highlands and high jungle until age 26 with 2 years of military service during that time. Subsequently, he travelled all over the country as an outdoor antenna installer which required him to sleep on the ground whenever working in the countryside. Currently living in Lima in a rented room with electricity but no running water or sewage. No known TB contacts, no sexual risk behavior

Physical Examination: HR 70x’ irregular, RR 18x’, BP 110/80, afebrile. Chest: Clear to auscultation bilaterally, no crackles. Heart: irregular rhythm, II/VI systolic mitral regurgitation. No jugular venous distension. Abdomen: normal bowel sounds, soft, non-tender, non-distended. No hepatomegaly. Neurologic: Awake, alert and oriented in time, space and person. No focal deficits, no meningeal signs. Extremities: no lower extremity edema.

Laboratory: WBC 7.16 (0, 47.6, 15.2, 1, 7.1, 29.1), Hct 44%, Hb 14.5 g/dL, platelets 253 000. Urea 38 mg/dL, creatinine 0.9 mg/dL, AST 22 U/L, ALT 52 U/L. Stools: Strongyloides stercoralis 1+ Rhythm strips from a 24-hour holter monitor (Image A) and a transthoracic echocardiogram (ImageB) are shown.

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator / Sofia Zavala, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Chagas cardiomyopathy
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Discussion: Two independent confirmatory antibody tests (ELISA and IFA) were positive for T. cruzi infection. On further questioning the patient recalled having been rejected for blood donation in 2014 due to a positive serology for Chagas; no further counseling was done and a cardiac evaluation was not performed. He does not recall having had contact with triatomine bugs and denied having Romaña’s sign at any time. However, his father states the presence of triatomines in the town where the patient grew up which is in a known endemic area.

His EKG and echocardiographic findings are non-specific and indicative of cardiomyopathy in general. Report of the Holter monitor: basal sinus rhythm, minimum HR 49x’, maximum HR 152x’. 13% of beats were ventricular, <1% supraventricular. Ventricular premature beats and non-sustained ventricular tachycardia (Image A). Report of the transthoracic echocardiography: Moderate mitral insufficiency due to mitral ring dilation after left ventricular dilation (Image B). Left ventricular and auricular dilation with global hypokinesis of the left ventricle, no apical aneurysm. Moderate dilated cardiomyopathy with mild systolic dysfunction, ejection fraction 48%.

T. cruzi is a single-celled protozoan found in two forms in infected humans. The infective trypomastigotes are found in the acute phase of disease circulating in the bloodstream. After the trypomastigotes infect muscle, nerve and other cells, they transform into small 3-micron intracellular amastigotes as the infection enters the chronic phase. Amastigotes replicate slowly by binary fission and are released after host cell rupture to infect other host cells. Initial human infection occurs when the vector, large triatomine bugs (5-45 mm in length, see Image C (take from previous case), take a blood meal at the end of which they defecate on the victim. The victim then self-inoculates with trypomastigotes present in the feces by rubbing on the irritated spot and the parasites enter by any small break in skin integrity or often through intact mucosal tissues such as the conjunctivae.

In the acute stage of infection, the clinical manifestations can vary widely. Most infections are asymptomatic, up to 20% have a mild undifferentiated febrile syndrome, and less than 5% have a severe or fatal illness that is usually associated with myocarditis, heart failure or meningoencephalitis. An inoculation chancre or chagoma is seen in about half of cases, and when the entry is via the conjunctiva, unilateral bipalpebral orbital edema (Romaña’s sign) is seen. Non-specific EKG changes are common, with evidence of myocarditis in more severe cases. The severe conduction abnormalities seen in chronic disease are uncommon in acute disease.

Patients in the chronic phase of disease have progressive infection of myocardial and autonomic nervous tissue and present with cardiomyopathy, cardiac conduction abnormalities and gastrointestinal disease, including megaesophagus and mega-colon. The alarmingly poor survival curves in individuals who manifest clinical cardiac disease have now been clearly elucidated [N Engl J Med. 2006 Aug 24;355(8):799-808]. Major risk factors for mortality in these patients are clinical heart failure, evidence of left ventricular dilatation or systolic dysfunction, and non-sustained ventricular tachycardia. This patient has a Rassi score >12, indicating a 10-year mortality of 85%. Unlike the acute phase, where parasites are present in circulating blood, diagnosis of chronic cases can be difficult and usually depends on serology or, optimally where available, PCR of blood.

Chronic Chagas’ heart disease usually presents initially with biventricular heart failure and then other complications later during disease progression. Frequent presenting symptoms are dyspnea on exertion, fatigue, palpitations, dizziness, syncope and edema due to heart failure, cardiac arrhythmias, and thromboembolism. Chest pain frequently occurs. Typical physical findings include murmurs of tricuspid/mitral regurgitation, split S2 (bundle branch block) and a diffuse apical thrust (apical aneurysm). Manifestations of right-sided heart failure often predominate. Any type of arrhythmia may occur, including sinus node dysfunction, intermittent complete atrioventricular block (RBBB most common) and complex ventricular arrhythmias. Ventricular arrhythmias and AV block frequently occur together. In advanced disease low QRS voltage is common. Atypical chest pain is common with or without heart failure but may mimic angina. Chagas’ heart disease requires presence of parasites in myocardial tissue and reflects an aberrant immune response. Endomyocardial biopsy is rarely necessary for diagnosis.

Human Chagas’ disease is found in all countries of the Americas from the southern USA to Argentina and Chile. The majority of the 10 million infected individuals are found in Brazil, though Bolivia has the highest seroprevalence rates. There are more than a hundred species of triatomine bugs in the Americas but most human disease is due to Triatoma infestans, Rhodnius prolixus, and Panstrongylus species. The vectors generally live in thatched roofs and cracks in the walls of poorly constructed homes in impoverished rural areas. More than 100 mammal species can act as reservoirs including dogs, cats and guinea pigs. In Perú, Chagas’ disease has been described with highest risk in the south, but reports of the disease in the Amazon jungle and highland areas of the north and centre of the country have occurred (General Office of Epidemiology, Peru, Report 2016)

Both benznidazole, usually considered the drug of choice and the alternative drug nifurtimox are generally poorly tolerated. However, alternative dosing strategies to conventional regimens have been proposed and are being refined [N Engl J Med. 2015 Nov 5;373(19):1882. doi: 10.1056/NEJMc1510996]. Peruvian guidelines mandate treatment of all patients regardless of symptoms. Our patient received Nifurtimox with only gastrointestinal side-effects, due to limited supply of benznidazole which occurs in many endemic countries. Anti-arrythmic drug therapy is being managed by a cardiologist.

University of Alabama at Birmingham

Gorgas Case 2017-08

Universidad Peruana Cayetano Heredia
The patient was seen in the Internal Medicine Service of the Cayetano Heredia National Hospital in Lima, Peru.
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History: 32-year old male presented to the ED with 8 months of abdominal pain and bloody diarrhea. The illness began with colicky mid-abdominal pain with 4/10 intensity, 3 times per day. 5 months before presentation liquid stools 2-3 times/day without mucus or blood began. Symptoms progressed and by 3 months before presentation the abdominal pain increased to 7-8/10 and he was having 5-6 bloody stools per day, associated with anorexia and weight loss of 10 kg. A colonoscopy and biopsy 1 month prior to presentation resulted in a diagnosis of Crohn’s disease and treatment with steroids and sulfasalazine without improvement.

One month before presentation, intermittent fever, productive cough, pallor, palpitations, dyspnea and fatigue led to his presentation to us. He denies any skin or mucosal lesions. Past medical history relevant for a diagnosis of external hemorrhoids on 2016, treated with topical creams. No surgeries or previous hospitalizations.

Epidemiology: Born and currently living in Moyobamba, a city in the high jungle, in a house with running water but no electricity or sewage, no animals at home. He works at his farm since age 16 and has coffee and rice crops, cattle, pigs and dogs. 3 years ago, one of his cows died of anthrax; he did not perform an autopsy.

Physical Examination: BP 120/80 mmHg, HR 117, RR 19, afebrile, SO2 98%, FIO 21%
Moderately ill appearing, with some wasting.
Lymphatic: multiple 1cm lymph nodes in the retroauricular, submandibular, anterior and posterior cervical, axillary, epitrochlear and left inguinal chains. Lymph node mass in the right inguinal chain.
Chest: decreased breath sounds on the right lung base, no crackles.
CV: regular rate and rhythm, tachycardic.
Abd: +BS, soft, non distended. Diffuse tenderness to palpation, liver was felt 5 cm BRCM. No peritoneal signs, negative Murphy and Mc Burney signs.
Digitorectal exam: no occult blood.
Neuro: awake, alert, oriented. No meningeal signs, no nuchal rigidity.

Laboratory: CBC: Hb 5.6, Hct 19%, mycrocitic, hypochromic. WBC 12.0 (0 bands, 73 segmented neu, 1.1 eos, 0.1 baso, 8.1 mono, 17 lymph). Platelets 767 000. ESR 49, CRP 96.
Glucose 72 mg/dL, urea 21.9 mg/dL, crea 0.7 mg/dL. Ca total 7.8 mEq/L, Na 136 mEq/L, K 4.08 mEq/L, Cl 106 mEq/L.
Total prot 4.8 g/dL, alb 2.2 g/dL. AST 18 U/L, ALT 52 U/L, AP 68 U/L, GGT 32 U/L, LDH 346 U/L. Normal bilirrubins.
Stools for ova and parasites: Negative.
Serology for HBsAg, HIV and HTLV-1: negative.
Sputum AFB: negative PPD: 0mm
Chest X-ray (Image A and B), abdominal CT (Image C), and colonoscopy (Image D; ileocecal valve) and (Image E; colon) are shown.  

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator / Sofia Zavala, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: P. brasiliensis, Chronic multifocal form
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Discussion: On biopsy of colonic lesions, a dense chronic inflammatory reaction with granuloma formation with yeast forms of varying sizes, with some yeast chains within and outside of multinucleated giant cells was observed [Image F]. A Grocott stain showed yeast cells of different sizes with peripheral budding [Image G]. A touch prep of one of the colonic biopsies identified yeast cells typical of P. brasiliensis in a KOH preparation. Subsequent sputum, urine and stool samples tested positive for yeast cells in KOH preps. Image H shows a mother cell with multiple peripheral daughter cells mimicking a pilot´s wheel typical of P. brasiliensis.

The CXR was reported as suggestive of micronodular involvement [Image A and B], no chest CT scan is available. Hepatosplenomegaly is the main finding on the CT abdomen [Image C]. The colonoscopy disclosed punched out ulcers with raised edges and a fibrin background at 15, 10 and 5 cm from the ileocecum valve, the valve itself looked edematous and erythematous, with erosions and small ulcers [Image D]. The cecum showed an eroded mucosa with loss of the normal vascular pattern [Image D]. Multiple longitudinal ulcers with irregular and edematous edges on a fibrin base, some of them with necrotic areas and spontaneous bleeding, were seen along the rest of the colon [Image E]. Punched out ulcers were observed in the rectum. The upper endoscopy was normal.

The diagnosis of Crohn´s disease was unlikely in this patient based on the epidemiology, rarity of this disease among Peruvians, but mostly on the lack of response to treatment and on infrequent clinical manifestations for Crohn´s disease seen in this case, such as generalized lymphadenopathy and lung involvement.

The chronic form of paracoccidioidomycosis most often involves pulmonary disease with oral mucosal involvement as a frequent complication [Gorgas Case 2004-05]. The differential diagnosis for the lung disease includes: TB, histoplasmosis, lymphoma, cancer and cryptococcosis. The typical radiographic pattern of paracoccidioidomycosis is with bilateral mixed infiltrates (alveolar and interstitial), mainly located in the middle and lower lobes. Interstitial lesions may have miliary (as in this case), nodular or fibronodular patterns. Other patterns observed in these patients are hilar and mediastinal lymph node enlargement, cavities, and calcified lesions. Extrapulmonary disease is found in over 70% of cases and may involve skin, mucous membranes, lymph nodes, adrenals, abdominal organs and CNS (in 9-25%).

Gastro-intestinal seeding in paracoccidioidomycosis results from disseminated abdominal lymph node involvement [Gorgas Case 2009-10]. It is rarely recognized in life due to nonspecific clinical manifestations that can resemble other conditions such as amebiasis, balantidiasis [Gorgas Case 2002-07], tuberculosis, cancer or inflammatory bowel disease, as in this case [J Clin Gastroenterol 2011;45:87-91]. Ulcers due to typhoid fever are usually in the ileum or proximal colon and would be preceded by a progressive febrile illness over weeks without diarrhea [Gorgas Case 2009-04]. Involvement of the entire gastrointestinal tract has been reported, from the esophagus to the rectum. However, small and large intestine involvement is most commonly reported. Autopsy studies documented 10-30% of intestinal involvement; the ileocecal segments are the most commonly affected areas Ano-rectal disease is reported in 2% [Rev Soc Med Trop 2001;34:583-6] [Gorgas Case 2005-12]. The disseminated disease observed in this case with pulmonary, lymph node and gastrointestinal involvement might have resulted at least in part due to iatrogenic use of steroids.

Paracoccidioidomycosis, also known as South American blastomycosis, is found in humid forested or lush green areas of the Americas from Southern Mexico south to Uruguay and Argentina. It appears to be most common in Brazil. The exact habitat of the organism is unclear but transmission is most often described as being entirely by airborne inhalation. Travelers spending less than 6 months in an endemic area are unlikely to acquire paracoccidioidomycosis.

Sulfonamides, itraconazole, and amphotericin B are all effective therapies. Amphotericin should be reserved for severe cases such as this one. For typical cases, itraconazole 100-200 mg/day for 6-9 months is regarded as the treatment of choice when it is available and affordable. Relapses are common with less than 6 months therapy and expert opinion is now that 1 year is not necessary. This patient was scheduled to start amphotericin B but due to economic constraints he was started on itraconazole.

University of Alabama at Birmingham

Gorgas Case 2017-07

Universidad Peruana Cayetano Heredia
The patient was seen in the intermediate neonatal care unit of the Cayetano Heredia National Hospital in Lima, Peru.
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History: A 23-day old preterm infant with an estimated gestational age of 32 weeks and a birth weight of 1360g, delivered at home from a 19 year-old mother (G3P2) without prenatal care, presented sudden onset tachycardia, fever, respiratory distress with borderline desaturation while being admitted at the intermediate neonatal care unit. He was initially brought by his family to the ED 2 hours after delivery with respiratory distress and hypoglycemia and was subsequently treated in intensive care with 5-days of antibiotics until neonatal sepsis was ruled out. He improved gradually and was tolerating room air until this sudden deterioration for which he was readmitted to the Neonatal ICU for oxygen support and further testing.

Epidemiology: Product of an uncomplicated pregnancy, dates unknown. UTI treated with vaginal medication 1 week prior to delivery. Two days of contractions with spontaneous rupture of membranes 12 hours before vaginal delivery. As reported by midwife, amniotic fluid was clear, placenta intact and completely expelled. Anthropometrics were all adequate for his estimated gestational age of 32 weeks. Immediately post-partum, the mother was found to be tachycardic, febrile and with vaginal bleeding and underwent puerperal curettage. She did not directly breast feed her infant during the hospitalization. Mother lives in San Juan de Lurigancho, Lima. Housewife, no risk factors for HIV infection, no history of recent travels.

Physical Examination: HR 174, RR 58, T 36.8ºC, sO2 91% (FiO2 0.21). Moderately ill infant with respiratory distress. Skin: warm, dry, mild pallor. Capillary refill less than 2 seconds.Lungs: symmetrical chest, subcostal retractions. Normal breath sounds, no crackles..Heart: regular rate and rhythm, no murmurs. Abdomen: Distended, bowel sounds present. Liver 1cm below right costal border. Neurologic: somnolent, decreased reactivity to tactile stimuli. Axial and appendicular hypotony, weak suction.

Laboratory: Hb 12.5 g/dL, Hct 35%. WBC 21.6 (2 bands, 54 neutrophils, 4 basophils, 1 eos,, 11 monos, 25 lymphs). Platelets 386 000. Blood type: O +, Mother: O+. Urea 16 mg/dL, creatinine 0.5 mg/dL. Na 137 mEq/L, K 5.04 mEq/L, Cl 102 mEq/L. AST 19 IU/L, ALT 15 IU/L, AP 365 IU/L. ABG: pH 7.347, pCO2 35.1, pO2 78.9, sO2 97.5%, HCO3 18.7. Urinalysis: WBC 0-3/hpf, RBC 0-2/hpf, few epithelial cells. Lumbar puncture: WBC 2/hpf (100% neutrophils), RBC 300/hpf, glucose 43, protein 171. Gram stain: negative. PPD: negative. Abdominal ultrasound: liver was normal, no hydronephrosis, no free fluid in the abdominal cavity. Chest X-Ray (see Image A).  

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator / Sofia Zavala, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Mycobacterium tuberculosis, congenital form.
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Discussion: On repeat testing, a gastric aspirate from the infant was positive for AFB (3+). Mother and baby were both HIV negative. Investigation of the mother, who remained febrile after the curettage, included chest X-ray and CT (Image B, C) showing a diffuse micronodular pattern. A pelvic CT (not shown) showed a large heterogeneous uterus which on examination after hysterectomy with bilateral salpingectomy, showed a chronic granulomatous process with giant multinucleated cells in the endometrium, myometrium (Image D) and Fallopian tubes (Image E). In addition, vascular emboli of tissue with granulomatous reaction in the parametrium (Image F) were seen though Ziehl-Neelsen stain was negative. The mother remained febrile after surgery. The diagnosis of miliary tuberculosis in the mother with genital involvement and the finding of AFB in the child led to the diagnosis of congenital tuberculosis and the need to start antituberculous therapy (RIPE) in both.

Congenital tuberculosis is the perinatal transmission of M. tuberculosis. It is thought to be acquired in any of the following ways: transplacentally, where the primary complex is found in the liver; by aspiration of infected amniotic fluid during birth, with the lungs as the primary focus, or ingestion of infected amniotic fluid, where the primary infection site is in the gut. [N Engl J Med. 1994; 330:1051–4].

The differential diagnosis in a newborn presenting with this clinical syndrome should include neonatal sepsis, toxoplasmosis, rubella, CMV, HSV (TORCH) , other congenital infections consider within the TORCH complex as others (O) including Syphilis, Parvovirus B19, VZV; HIV. In preterm newborn with respiratory distress consider hyaline membrane syndrome (respiratory distress syndrome).

The Cantwell criteria for congenital TB are:
Proven tuberculosis in the infant plus one of the following,
• Lesions occurring in the first week of life
• A primary hepatic complex
• Maternal genital tract or placental tuberculosis
• Exclusion of postnatal transmission by thorough investigation of contacts.

Although in our case, there was no evidence of a liver primary complex on ultrasound, the presence of genital tuberculosis in the mother supports also transplacental acquisition of MTB.

The diagnosis of tuberculosis in an infant is based on a TST result, which is often negative, and a chest radiograph or other radiologic studies in a patient with a compatible clinical syndrome. Microbiological confirmation should be made whenever possible by examining specimens such as gastric aspirate, ascitic fluid, endotracheal aspirate, middle ear fluid, and CSF [Pediatrics 1980;66:9804].

In infants, the clinical presentation of tuberculosis is characterized by failure to thrive, fever and night sweats. However, tuberculosis in a newborn is harder to recognize. Signs and symptoms of congenital tuberculosis usually develop at 2–3 weeks of age and include he-patosplenomegaly (76%), respiratory distress (72%), fever (48%), lymphadenopathy (38%), abdominal distension (24%), lethargy or irritability (21%), ear discharge (17%) , or feeding problems as seen in other neonatal infections [Pediatr Pulmonol 2011;46:121524]. BCG is contraindicated in preterm newborns with less than 34 weeks of gestational age or birth weight of less than 2 KG.

Congenital tuberculosis should be suspected and investigated whenever: (1) a newborn does not respond to conventional treatment for pneumonia or sepsis, (2) mothers are diagnosed as having tuberculosis and their babies have nonspecific symptoms and (3) a newborn presents unexplained fever and hepatosplenomegaly at 2–3 weeks of age [J Trop Pediatr 2007;53:1358]. Also, many infants with congenital tuberculosis may have an abnormal chest radiograph, miliary (as in our case) being the most common pattern [Clin Perinatol. 1997; 24:107 –27].

Congenital tuberculosis has a very high mortality rate of up to 50% among the patients presenting before 4 weeks of life. (Ref) Due to the difficulty of establishing the diagnosis early in life, we stress the need for high index of suspicion and early diagnosis and prompt treatment, especially in high prevalence settings. In some cases, empiric treatment should be a consideration, particularly in resource-limited settings where diagnostic capacity is reduced.
Medical therapy for congenital tuberculosis is the same as for adult tuberculosis 6 – 9 months and depending on national guidelines. Dosing should be weigth base and revise at each follow up visit [WHO - Guidance for national tuberculosis programmes on the management of tuberculosis in children – 2nd ed,]. The mother must be adequately treated in tandem.

We would like to thank Theresa Ochoa MD, Universidad Peruana Cayetano Heredia, for providing insightful case discussion.

University of Alabama at Birmingham

Gorgas Case 2017-06

Universidad Peruana Cayetano Heredia
The patient was seen on the wards of the Cusco Regional Hospital.
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History: 44 year-old female presented to the outpatient clinic complaining of a 2-week history of 2 cm itchy migratory subcutaneous nodule initially arising over the epigastric region. She had earlier presented to another hospital with right upper quadrant pain. Over the next 2 weeks, the lesion migrated towards the left breast and the patient was admitted to undergo excision of the lesion. She denied having cough, fevers, weight loss or other constitutional symptoms.

Epidemiology: Born and lives in Cusco city where she works in an office. Wears shoes and doesn't swim. Her diet includes mainly green leafy vegetables and fresh vegetables and herbal extracts. Admits eating ceviche occasionally. No known TB exposure or specific HIV risk factors. Has a healthy child at home.

Physical Examination: Normal vital signs, afebrile. Chest: Breath sounds were present bilaterally, no wheezing or crackles. Heart: RRR, no murmurs, rubs, or gallops. Abdomen: Bowel sounds were present, the abdomen was soft, non-tender without hepatosplenomegaly. Skin: 3-cm nodule at the inferior border of the left breast, slightly tender to palpation, mobile and hyperpigmented. Several hyperpigmented macules in the epigastrium and left upper quadrant (Image A). No lymphadenopathy. Rest of the exam was unremarkable.

Laboratory: WBC 7.5 (50 neutrophils, 17 eos, 6 monos, 26 lymphs). Hb 11.8, Hct 38, MCV 76.2, MCH 24.2. Platelets 220, 000. Glucose 87. Renal and liver function were normal. Ultrasound of the liver 2 weeks before admission is shown (Image B).  

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator / Sofia Zavala, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Fasciola hepatica, chronic form with ectopic cutaneous lesion. Parenchymal form.
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Discussion:The liver ultrasound (Image B) shows intra-hepatic bile duct dilatation. During an ERCP, 3 adult Fasciola hepatica parasites were removed. Her stools were positive for ova of F. hepatica. The nodule was excised (Image C) and a juvenile F. hepatica was found in the adjacent tissue (Image D). See case 2015-05 for histologic demonstration of this parasite. Of note, her husband was diagnosed with acute fascioliasis 3 months earlier and was treated with triclabendazole. She had been treated at the same time with 2 courses of triclabendazole but her stools had remained positive prior to the ERCP.

Fasciola hepatica is a trematode (fluke or flatworm) zoonosis in which the adult parasites inhabit the large biliary ducts of their definitive host. 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 or alfalfa.

Recent data, however, also suggests waterborne transmission. After ingestion by a human or animal definitive host, the metacercariae excyst in the duodenum and larvae penetrate the intestinal wall and subsequently migrate directly into the liver via Glisson’s capsule and embark on a destructive migratory process through the hepatic parenchyma for 3 to 4 months until they reach large biliary ducts, where they then mature to adults.

The mature adults are from 1 to 3 cm long and attach to the biliary epithelium by a single ventral sucker. Direct visualization of adult forms is uncommon, however characteristic eggs can be seen on stool examination. Patients who present in the early migratory phases of infection prior to maturation of the worm do not pass eggs in the stool. Specific serology is the test of choice in these acute cases, but most tests are produced from crude antigens and have significant results variability.

The distribution of F. hepatica is cosmopolitan, but is by far the most common in cattle-raising areas where herbivores are common definitive hosts. Other important definitive hosts are goats, sheep, horses, llamas, vicunas, and camels. The Altiplano regions of the Peruvian and Bolivian Andes are highly endemic, with human prevalence rates as high as 67% in some villages. In the agricultural areas near Cusco, the prevalence in children 3 to 12 years old is 11% by stool microscopy and Fas2 ELISA [Am J Trop Med Hyg. 2014 Nov;91(5):989-93]. 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 especially and the population is reluctant to adopt this simple measure. Emoliente, a local tea-like drink that uses drops of watercress juice to provide a bitter flavor is a frequent vehicle of infection.

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 produce few or no symptomatic but some patients develop chronic manifestations including right upper quadrant pain, nausea, vomiting, and hepatomegaly. However, even asymptomatic infected children may develop anemia. 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. Malignant degeneration and cholangiocarcinoma such as results from chronic infection with the oriental liver fluke Clonorchis sinensis has not been reported with F. hepatica. We have reported a case series with clinical findings and evolution of patients with acute disease [Am J Trop Med Hyg. 2008 Feb;78(2):222-7]. Of note, the vast majority of acutely infected subjects in the community are not diagnosed or are not symptomatic enough to seek medical attention. Please see Gorgas Case 2005-02 for a CT image of another example with the typical larval tracks seen in acute disease.

The differential diagnosis of eosinophilia with migrating paniculitis includes gnathostomiasis, paragonimiasis, loiasis, and cutaneous larva migrans. 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. Paragonimiasis, loaisis, and cutaneous larva migrans are not reported in Cusco city. Gnatosthomiasis has been diagnosed in Cusco before, but fascioliasis is far more common in the area. Migratory subcutaneous nodules in fascioliasis are uncommon, but the diagnosis should be suspected in subjects from endemic areas presenting with eosinophilia.

Fasciola hepatica is the only trematode infection for which praziquantel is not the drug of choice. Triclabendazole is the only highly effective medication recommended for the treatment of acute and chronic Fasciola infection in children and adults. The 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 through Ministry of Health clinics in endemic areas. In the U.S. the drug is available from the CDC Parasitic Drug Service. The recommended dosage is 10 mg/kg with a fatty meal once or twice (separated 12-24 hours). In initial studies at our institute the cure rate was 96%, however the response rates have been lower in recent experience. Triclabendazole resistance is already a significant problem for the livestock industry in developed and developing countries including Peru where high rates of resistance have been reported in cattle. Resistance in human is emerging with cases reported from The Netherlands, Turkey, Chile, and Peru. Among children in Cusco, the response rates to a single dose of triclabendazole can be as low as 60%. A recent case series from Cusco describes highly resistant fascioliasis failing to respond to several courses of triclabendazole and nitazoxanide (PLoS Negl Trop Dis 2016;10(1): e0004361). Although, randomized trials suggest nitazoxanide response rates between 40%-60% and case series from Mexico report 100% response, our experience in Peru shows very low effectiveness.

We would like to thank Miguel Cabada MD, University of Texas Medical Branch, for providing insightful case discussion.

University of Alabama at Birmingham

Gorgas Case 2017-05

Universidad Peruana Cayetano Heredia
The patient was seen on the wards of the Cusco Regional Hospital.
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History: 12 year old girl who presents with headache and seizures. She was healthy until aged 9 years when she had a single tonic clonic seizure and then remained asymptomatic until 2 months prior to admission, when her mother noted a second seizure. She then developed global and pulsatile headaches unresponsive to analgesics. Three days prior to admission, she developed a more severe headache, associated with some dysarthria and photophobia.

Epidemiology: Born and lived all her life in Cusco city in the Andean highlands. No illness in the family. No known TB contacts.

Physical Examination: Blood pressure 120/70 pulse 89, afebrile. She was alert, oriented in no acute distress. Pupils equal and reactive, fundi clear. Physical examination and a detailed neurologic examination were normal.

Laboratory: Hb 16.0 Hct 48.4 WBC 10.0 (normal differential, no eos) platelets 207 Glucose 96; Urea 21; Cr 0.67; normal liver enzymes. Normal Chest x-ray. Non-contrast head CT is shown (Images A,B,C).  

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator / Sofia Zavala, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Neurocysticercosis due to Taenia solium. Parenchymal form.
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Discussion:Diagnosis of neurocysticercosis can be problematic, especially in patients with one or 2 lesions. The imaging studies usually show cystic lesions (as in this case), but often do not demonstrate the scolex, which can be diagnostic. Studies in southern India of patients with single enhancing lesions were used to develop a clinical definition of cysticercosis. They found that, in patients with seizures, the combination of a single round lesion less than 2 cm in diameter with no midline shift, no symptoms or signs of other diseases, and a non-focal neurologic examination was highly predictive of neurocysticercosis. In a prospective study, this definition had a sensitivity of 99% and a specificity of 98.9% for cysticercosis [Rajshekhar V et al. Acta Neurol Scand 1987;96:76]. This definition has been incorporated into current guidelines for diagnosis [Del Brutto OH et. al. J Neurol SCi 2017;372:202]. Our patient had 2 lesions rather than 1, but they were clustered together and essentially met those criteria. The non-contrast CT scans are shown. Image A is s sagittal view that shows two cysts close to each other in the right occipital area without obvious edema. Image C is a coronal view that shows the two cysts lesions. While there is no definite scolex, the focal area of increased density on the edge of the cystic area suggests a scolex. The scolex is the head of the larval T. solium tapeworm. Typical viable lesions with scolex are shown in image D (from another patient).

Cysticercosis is infection with the larval stages of the human pork tapeworm Taenia solium. Humans acquire cysticercosis after ingesting eggs of T. solium in material contaminated with feces originating in human tapeworm carriers. Humans that do not eat pork can get cysticercosis. Ingestion of contaminated pork results in humans getting an adult intestinal tapeworm – not cysticercosis. Cysticercosis is common in many developing countries and very common in rural agricultural areas of Perú. In developed countries, the long-lived cysticerci are increasingly seen as immigration from affected areas rises. Occasional transmission by tapeworm carriers to those who have never left non-endemic countries is reported. Ingested T. solium eggs hatch in the stomach and are then carried to the muscles and other tissues where the larvae encyst and reach their usual size of about 1 cm within a few months.

Separate clinical, diagnostic, and therapeutic considerations apply to patients with the 4 forms of neurocysticercosis: intraparenchymal, ventricular, sub-arachnoid or spinal. See Gorgas Cases 2014-10, 2011-06, 2007-02, and 2006-04 for discussion of these presentations.

The cysticerci seem able to evade the immune system and are thought to remain viable for several years without causing any inflammatory response, so that most infected patients are asymptomatic for years alter infection. Most clinical symptoms are the direct result of inflammatory responses that accompany the eventual cyst degeneration, but most patients likely remain asymptomatic even as cysts die. Epileptic seizures are the primary or sole clinical manifestation in up to 80% of symptomatic patients. In endemic regions new onset seizures in teenagers or young adults is most likely due to neurocysticercosis. Cysticerci can also cause symptoms because of mass effect, impingement on a vital structure or, especially if the cyst is intraventricular, blockage of CSF circulation.

Patients with one or 2 parenchymal cysticerci have a relatively benign form of the disease. Even without specific treatment, the disease is usually self-limited. Based on that some clinicians had recommended not using antiparasitic treatment. However, the time course is often prolonged. Two meta-analyses of randomized trials have been published on treatment of patients meeting the definition of solitary cysticercal granulomas [Zhao BC et al. PLoS Neg Trop Dis 2016;10(2):e0004418; Otte WM et al. Neurology 2013;80:152] . Overall, the radiographic resolution is more rapid and the number of seizures during the 6 months after diagnosis is improved in patients treated with a short course of albendazole and corticosteroids (typically 1-2 weeks). However, that treatment did not decrease the proportion of patients who subsequently developed calcifications on CT scan and did not impact the frequency of seizure more than 6 months after presentation.

Interestingly, most patients with a single lesion resolve without forming calcifications. In those with few seizures and radiographic resolution (which usually occurs within 6 months of albendazole treatment), anti-epileptic drugs can safely be tapered off.

Parenchymal neurocysticercosis with more than 2 viable and/or degenerating cysts should be treated with Albendazole 15 mg/kg per day (max. 800 mg/day) + Praziquantel 50 mg/kg per day + Dexamethasone 0.1 mg/kg/day beginning 1 day prior to anti parasitic drugs] x 10 days ± Anti-seizure medication if needed [Garcia HH et. al. Lancet Infect Dis 2014;14:687]. Some data suggest that higher doses of corticosteroids may decrease early seizures. Albendazole alone without praziquantel is likely adequate if only 1-2 cysts on an MRI. Dead, calcified cysts only require no antiparasitic treatment. Our patient responded rapidly to albendazole and steroids.

We would like to thank Clinton White MD, University of Texas Medical Branch, for providing insightful case discussion.

University of Alabama at Birmingham

Gorgas Case 2017-04

Universidad Peruana Cayetano Heredia
The following patient was admitted to the Pediatric Intensive Care Unit at the Cayetano Heredia Hospital in Lima, Peru.
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History: A 2.5 year-old female presented to a local hospital with a 6-day history of fever followed by neurologic symptoms. Despite a negative thick smear, a community healthcare team started empiric treatment for malaria with cloroquine and primaquine on the third day of non-specific fever that had failed to respond to anti-pyretics. On the third day of illness, ataxia and trembling of the lower extremities began and later progressed to the upper extremities. Lower extremity weakness then progressed to an inability to stand unassisted. On day 6, anorexia and vomiting began until on day 7 when she began to have difficulty swallowing, increased salivation and stuttering speech. On day 8 she was still febrile, became hypoactive, unable to follow instructions, and finally somnolent (possible status epilepticus) before transfer to our hospital. No prior medical history.

Epidemiology: Born and raised in an agricultural family in the Mayapo community, province of La Convencion in the jungle of Cuzco department. She had no history of malaria, was unvaccinated for yellow fever, and had no known exposure to TB. She had received 1 ml. doses of tissue culture rabies vaccine 11 and 4 days prior to the onset of fever as part of a pre-exposure vaccination campaign in her community following some earlier encephalitic fatalities.

Physical Examination (arrival at our ER): HR 108, RR 32, BP 89/33 mmHg, T 37ºC, SatO2 95% Acutely ill patient. Skin: no rash. Chest: diffuse rhonchi bilaterally. CV: regular, tachycardic, multifocal murmur II/VI. Abdomen: bowel sounds present, no tenderness, no pain. Neurologic: Glasgow 12/15, somnolent, not following verbal commands. Opens her eyes after painful stimuli and localizes pain. Hypotonic, muscle strength not assessed. Normal reflexes, Babinski negative, no clonus, Hoffman negative. No meningeal signs. Image A shows the child in the ICU.

Laboratory Examination: WBC 19.9 (2 bands, 73 segmented neutrophils, 3 eos, 7 monos, 15 lymphs), Hb 7.6 g/L, platelet count 494 000 /uL. Glucose 85 mg/dL, BUN 9 mg/dL, creatinine 0.3 mg/dL. Total protein 6.6 g/dL, albumin 3.2 g/dL. Total bilirubin 0.4 mg/dL AST 36 U/L, ALT 25 U/L, AP 166 U/L. CXR and MRI are shown in Image B and Image C. CSF: WBC 79 cells/hpf (90% lymphocytes), RBC 25 cells/hpf, glucose 51 mg/dL, protein 91 mg/dL. Malaria smear negative. 

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator / Sofia Zavala, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Paralytic rabies.
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Discussion: Giemsa stain of blood smear for Bartonella: negative. IgM ELISA for dengue, yellow fever, Oropuche, Mayaro, Venezuelan Equine Encephalitis: negative. PCR for rabies on nuchal skin biopsy and saliva: positive. Rabies neutralizing antibodies in serum: 2.2 IU/ml and neutralizing antibodies in CSF: 0.5 IU/ml. In general, in studies on dog rabies in Africa, rabies can be most efficiently diagnosed with PCR of saliva on 3 samples; if any are positive rabies is confirmed and will quickly guide the best course of action. A number of abnormalities on brain CT and MRI have been described in rabies but none is diagnostic and this patient had only non-specific cerebral edema.

Further detailed history determined that a mass pre-exposure vaccination campaign had been started after two cases of bat rabies were confirmed in her community. The parents reported that coincidentally, the patient had been bitten by a bat on the scalp at night despite using a mosquito net. As part of the mass vaccination campaign, she received a dose of rabies vaccine (tissue culture vaccine) two days after the bite and a second dose 7 days later, these two doses were actually intended for pre exposure prophylaxis.

Furious rabies is the more common clinical presentation of rabies in humans but this case, as with almost all cases transmitted by vampire bats, represents the less distinctive paralytic form of rabies disease. After prodromal symptoms, which include fever, headache and local paresthesias (not reported in this patient), an ascending flaccid paralysis with pain and fasciculation in the affected muscles and mild sensory disturbance ensue. Symptoms tend to begin around the site of the bite in the affected limb. A careful search for the telltale bite should be undertaken (example from another patient in Image D). Paraplegia and sphincter involvement then develop and the terminal event is usually a fatal paralysis of the swallowing and respiratory muscles. Hydrophobia, common in furious rabies, is very rare. Survival from onset of disease may be several weeks if no complications ensue. Other possible diagnoses include HSV encephalitis and VEE, plus many other arboviral encephalomyelitides e.g Oropouche. Guillain Barré (ascending paralysis) and severe tetanus with autonomic instability may present with similar peripheral symptoms.

Rabies is caused by RNA viruses of the genus Lyssavirus. Classic Rabies virus (species I) is the most common of the 6 viral species in the that cause an identical rabies-like illness, and it is responsible for more than 55,000 human deaths annually. Outside of the Americas, most human cases are associated with domestic dog bites and exposures. Rabies virus is transmitted in the saliva inoculated by the bite of an infected mammal. In the Americas, bats and carnivores are the major reservoirs and multiple insectivorous bat species transmit the virus to humans in the United States. In Latin America, rabies is transmitted by the three species of vampire bat, especially Desmodus rotundus which are confined to middle/south America and some Caribbean islands. Wide circulation of rabies among vampire bats, which are efficient transmitters, throughout their geographic range occurs throughout Latin America has resulted in outbreaks, first confirmed in Trinidad (1925-32), and in a number of Latin American countries including Ecuador, Venezuela, Brazil as well as Peru. A variety of bat lyssaviruses in the genus circulate widely in bats in other parts of the world and have been associated with a relatively small numbers of cases of clinical disease identical to rabies.

In Peru, urban dog rabies has decreased dramatically since 1995 thanks to mass vaccination programmes notably in Lima and Callao. Most recently [INS 24/02/2017], canine rabies has recurred in Puno and Arequipa., and in 2014 the 14 cases in canines were restricted to Puno, Puerto Maldonado, and in 2015 an emergence of 10 canine cases occurred in Arequipa with 1 human case. A number of significant outbreaks of rabies in humans associated with vampire bat rabies have occurred throughout the jungle regions of the country over the past several decades. Four human cases of rabies were reported in Peru in 2015, one was urban rabies, but 15 cases were associated with vampire bat bites in 2016.

During epizootics of vampire bat rabies, cows (a preferential food source for vampire bats) become infected first and dying cattle with evidence of vampire bat bites often herald human outbreaks. Bat bites, most of which are un-noticed, unlike in our present case, are common in indigenous regions. Recently, it has been noted that 11% of healthy individuals randomly tested in Loreto had neutralizing antibodies to rabies (Am. J. Trop. Med. Hyg., 87(2), 206-215, 2012) indicating that sub-clinical and/or non-fatal infection with lyssaviruses is possible. Risk factors for bat exposure included age less than or equal to 25 years and owning animals that had been bitten by bats.

In managing patients with confirmed rabies encephalitis, the doctor’s primary responsibility is to palliate their terror, pain and distress. Intensive care might be considered if an American bat virus is thought to be involved (they may be less virulent), some vaccine was given before onset of encephalitis, rabies neutralising antibody was detectable early, and intensive care facilities are available. All these conditions were fulfilled in this patient who has now survived for >70 days after onset of symptoms but remains with serious neurologic impairment. The controversial Milwaukee protocol (frequently revised/updated) comprises a variety of interventions aimed at controlling dysautonomia, vasospasm and other commonly observed complications. It has no proven advantage over standard intensive care (J Neurol Sci 2014: 339: 5–7; Can J Neurol Sci 2016: 43: 44–51).

Neither rabies vaccine nor rabies immune globulin (not available in Peru) is of benefit after the onset of clinical rabies.

This case demonstrates the necessity of both RIG as well as vaccine for post-exposure prophylaxis. The vaccine dose given two days after the bite, though intended as a pre-exposure series, fits perfectly a frequent traveler scenario of an unvaccinated traveler being in a country with no RIG, getting a dose of vaccine within a day or 2 and then having to make the decision about continuing the trip or going home for RIG. If the traveler is a young adult it is sometimes necessary to get the family involved to ensure financial and other arrangements for the trip home.

We would like to thank, Professor David A Warrell FMedSci FRCP and Gorgas Course Professor Emeritus, University of Oxford; for providing insightful case discussion.

University of Alabama at Birmingham

Gorgas Case 2017-03

Universidad Peruana Cayetano Heredia
The following patient was seen in the outpatient department of the Tropical Medical Institute:
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History: 80-year-old male with a 16-year history of slowly progressive crusted lesions around the right knee. Patient initially presented with painless pruritic papules on the medial aspect of the knee. Papules spread gradually to the leg and to the thigh over approximately 6-months and then all became crusted and pruritic. No history of trauma elicited. No drainage at any time. Since then, the lesions have extended very slowly and no other skin lesions have been present anywhere else. No fever or constitutional symptoms. Significant difficulty in extending the knee has developed over the last 5 years with the development of subcutaneous fibrosis of the posterior aspect of the knee. He has not had medical evaluation during his illness and initially presented to our leishmania clinic.

Epidemiology: Lives and grew up in a rural city of the highlands of Huamalies, Huanuco. Works as a farmer harvesting corn, and potato, with exposure to animals including cattle, horses, guinea pigs and chickens. No HIV risk factors.

Physical Examination: Afebrile; normal vital signs. No lymphadenopathy. Extensive involvement of the entire right knee with plaques over the anterior and posterior aspects (Image A). Individual plaques had raised and erythematous borders with areas of central scarring and atrophy. Isolated new lesions on the thigh appeared rounded with erythematous crusted borders with sparing of central areas (Image B). Significant bridging on the lateral aspect of the knee (Image C). No lymphedema, no suppuration. Chest: clear. Abdomen: no hepatosplenomegaly. Neurological: normal.

Laboratory Examination (on admission): Hb: 12.6; WBC: 7800 (58 neutrophils; no eos). Normal biochemistry and urine. Normal chest x-ray and normal plain films of both legs and knees. Negative serological tests for HBV, HTLV-1 and HIV.

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator/Sofia Zavala, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus
Diagnosis: Chromoblastomycosis.
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Discussion: A 10% KOH preparation of a skin scraping of a crusted lesion (Image D) showed pigmented thick walled multi-celled structures called sclerotic bodies, medlar bodies, or muriform bodies which are diagnostic of chromoblastomycosis. Morphologically, muriform cells constitute an aggregation of 2 to 4 fungal cells with transverse and longitudinal septation. These are double-walled brown structures with a diameter of 4 to 10 μm that resemble copper pennies. Sometimes, thick and dark hyphae are identified. Cultures can be performed on Sabouraud agar or Sabouraud with antibiotics at 25° to 28ºC. The causative organisms grow slowly (25-30 days). Culture and pathology are pending.

Implantation or subcutaneous mycoses are a heterogeneous group of diseases and organisms that share the characteristic that they develop at the site of skin penetrating trauma. Etiologic agents of subcutaneous mycoses are divided into several clinical groups:

• The eumycetomas typically cause locally invasive purulent and destructive disease that will eventually destroy underlying soft tissue and bone while sparing nerve and vasculature. Sinus tracts with granule production is common. Madura foot and related lesions are caused by Madurella mycetomatis (by far the most common cause of Madura foot in Peru; produces dark granules), Exophilia sp. and Pyrenochaeta sp., as well as Fusarium and Acremonium (produce pale granules).

Phaeohyphomycosis is caused by dematiaceous (pigmented) fungi but is not limited to skin or subcutaneous tissue and is associated with a wide range of inflammatory responses mainly in the sinuses, lungs, and brain. Disseminated disease beyond skin is usually in compromised hosts. Most frequent causes are Exophilia jeanselmi, Wangiella dermatidis, and Bipolaria species. Hyphae are typically seen histologically.

• Chromoblastomycosis is characterized by papular lesions with chronic onset that progress (often over many years) to nodules or plaques most often with a hyperkeratotic verrucous surface. Feet, knees, lower legs, and hands are the most common sites of infection. Sclerotic bodies are typically seen histologically, and invasion or spread beyond the local subcutaneous tissue does not occur. The most common etiologic agents are Fonsecaea pedrosoi (moist environment) and Cladophialophora carrionii (dry environment), with Phialophora verrucosa, and Rhinocladiella aquaspersa being less common while a few cases due to the Exophiala genus have been reported. A recent review of 123 cases from Brazil confirmed that F. pedrosoi accounted for 80% of the isolates [PLoS NTD 10(11):e0005102].

Chromoblastomycosis occurs worldwide, including in the USA, but 70% of cases are estimated to occur in tropical areas due to the moist weather conditions. Most cases in Latin America are from the Amazon rainforest of Brazil, from Mexico, and from Costa Rica, but cases are reported from Colombia, Ecuador, Venezuela, Argentina, the Dominican Republic, and Cuba. Many cases are also reported from Madagascar and South Africa. Up to 90% of cases occur in males likely due to occupational factors. Chromoblastomycosis is most often an occupational disease that is strongly associated with agricultural activities.

Chromoblastomycosis lesions are clinically polymorphic and have a large differential diagnosis. Other considerations for a life-long subcutaneous indolent infection like this includes: sporotrichosis [Gorgas Case 2008-1], eumycetoma [Gorgas Case 2002-4] (no drainage with grains were reported in this case), lobomycosis (lacaziosis) [Gorgas Case 2005-3], subcutaneous zygomycosis, subcutaneous phaeohyphomycosis, botryomycosis [Gorgas Case 2003-4], leishmaniasis [Gorgas Case 2004-1], nocardiosis [Gorgas Case 2011-1], and cutaneous tuberculosis. Squamous cell carcinoma, leprosy and leishmaniasis are less likely.

Our patient is classified in the moderate group of illness based on an old classification system that takes into account 4 criteria: total area of involvement, number of lesions, complications and lack of response to prior treatment. Long-term complications include superinfections, ulceration and lymphedema.

Treatment of chromoblastomycosis is often difficult and is based on case report and case series; there are no controlled trials. Surgery is the best physical method for the treatment of chromoblastomycosis and excisional surgery is strongly recommended for all initial small and well-delimited cutaneous lesions. Surgery may also be used in conjunction with ITZ or terbinafine treatment. Cryotherapy, heat therapy, and laser therapy are also described. For medical therapy studies suggest that both Fonsecaea and Cladophialophora species are highly susceptible in vitro to several triazole compounds, including ITZ, voriconazole, posaconazole, and isavuconazole, but not to fluconazole, 5-flucytosine (5-FC), amphotericin B or echinocandins. Terbinafine also shows in vitro activity against Fonsecaea and other etiological agents [Clin Microbiol Rev 30: 233–276–276].

Itraconazole is uniformly considered the treatment of choice with terbinafine as second line. With very chronic infections like this one, itraconazole may induce significant scarring /fibrosis that impairs functionality of the extremity. Duration of treatment is no less than 1 year starting at 200mg tid for 3 days, then 200mg bid. Measurement of serum drug levels is recommended to improve outcomes. Response is observed after 3-4 months of therapy, sustained response is not always observed due to its fungistatic nature.

University of Alabama at Birmingham

Gorgas Case 2017-02

Universidad Peruana Cayetano Heredia
The following patient was seen in the outpatient department of the Tropical Medical Institute:
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History: A previously healthy 42-year-old female presented with a 3-month history of progressive painful and pruritic cutaneous lesions on the dorsum of the left foot. She initially noticed a painful and slightly pruritic papular lesion over the first metacarpo-phalangeal joint. During the following week, the lesion extended on the plantar surface of the foot towards the sole in a linear path that later blistered and increased to a size of 3 x 4 cm. She was treated with cephalexin and dexamethasone for a few days without improvement. One month into the illness the now markedly pruritic lesion began to migrate in the same linear path to the dorsum of the foot. No fever or systemic symptoms, no swelling in the groin.

Epidemiology: Lifelong resident of Lima. One week before the onset of symptoms she had returned from 11 days beach vacation in Cartagena de Indias, Colombia. She walked barefoot on different islands, beaches and swimming pools. She has 2 dogs at home.

Physical Examination: Afebrile. Chest clear. No lymphadenopathy or hepatosplenomegaly. Skin findings restricted to the linear serpiginous tracks on the left foot shown in Image A.

Laboratory Examination (on admission): WBC 7000 (57% segmented neutrophils, 2% eosinophils, 0.4% basophils, 6.4% monocytes, 34% lymphocytes). Hb 13.0 g/dL.

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator/Sofia Zavala, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus
Diagnosis: Cutaneous Larva Migrans due to Ancylostoma braziliense.
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Discussion: This is a clinical diagnosis with pathognomonic clinical findings as demonstrated in the Images [see review Lancet Infect Dis 2008; 8: 302–09–09]. Hookworm-related cutaneous larva migrans, is the term that describes the characteristic migratory dermatitis caused by initial invasion of the skin by the larva of animal or human nematodes. The larvae of the dog and cat hookworm Ancylostoma braziliense account for almost all of the clinically obvious skin lesions. Other hookworms infecting animals can invade and parasitize humans or can penetrate the human skin (causing hookworm-related cutaneous larva migrans), but do not develop any further (Ancylostoma caninum, Uncinaria stenocephala). Occasionally A. caninum larvae may migrate to the human intestine, causing eosinophilic enteritis.

Because Ancylostoma braziliense does not mature or complete its life cycle in humans, the immature larvae may wander superficially for up to several months before their spontaneous death. The larvae move up to 1-2 cm per day. Biopsy of the lesions is not recommended, as the larvae are rarely isolated. Usually the larvae have migrated ahead of any inflammatory response and it is difficult to know in what direction the larva has advanced. Cutaneous larva migrans is found in any moist warm climate and is found in the southeastern USA as well as throughout the tropics. In travelers, the highest prevalence is in those returning from Caribbean destinations, followed by southeast Asia, and Central America.

Larvae of human hookworm (Ancylostoma duodenale and Necator americanus) may cause an initial pruritic lesion but rarely migrate in the skin before traveling to the lung and then the intestine as they mature and complete their life cycle. In travelers the incubation period may last a month or even longer. Larvae usually migrate in the epidermis for 2–8 weeks to several months. Lesions are most common on the feet, buttocks, and thighs reflecting areas exposed to soil and sand in typical beach resort travelers.

Other causes of the clinical syndrome of creeping eruption include gnathostomiasis [see example in Gorgas Case 2003-01], which tends to cause more hemorrhagic and less distinct linear tracks, and strongyloidiasis, which causes a variant usually called larva currens. Larva currens occurs due to autoinfection whereby filariform larvae of Strongyloides stercoralis passed in the stool invade perianal skin and re-infect the same host. The lesions are usually in the perianal, buttock, or abdominal region only. The lesions are highly pruritic but have a predominant urticarial component and progress up to several cm per day. They may be present for several weeks. The subcutaneous filarial infection with Loa loa seen in west and central Africa causes a migratory and transient angioedema, predominantly around joints. Linear lesions are not found. Rare cases of cutaneous pili migrans have been found in travelers.

Treatment is with ivermectin 12 mg PO, which can be repeated once a day later, or with albendazole 400 mg PO for 3 days. Some cases present with folliculitis which requires more aggressive prolonged therapy [J Travel Med 2015; 22: 221–224]. Most clinicians prefer ivermectin [Clin Infect Dis. 2013 Oct;57(8):1155-7-7]. Thiabendazole topical therapy still mentioned in many textbooks is no longer used (and rarely available) and cryotherapy still used by some dermatologists is much less effective. Because of the fecal origin of the larvae, bacterial superinfection can result but antibiotics are generally only recommended if purulent infection is clinically present.

In our patient, treatment was started with Albendazole 200mg bid. However, on follow up 3 days later she reported a new tract with a vesicle and the treatment was changed to ivermectin.

University of Alabama at Birmingham

Gorgas Case 2017-01

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 17th 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.
Eduardo Gotuzzo and German Henostroza
Course Directors
The following patient was seen in the inpatient department of the 36-bed Tropical Disease Unit at Cayetano Heredia National Hospital in Lima, Perú.
Image A for Case 2017-01
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History: 59 yo male presented to the emergency room with a 13 day history of progressively spreading pain in his left foot. Four days prior to admission he noted neck stiffness with inability to move his head in any direction. One day prior to admission he had onset of episodes of generalized muscle rigidity and was brought to the local hospital. The family denies that the patient had fever, headache, odynophagia, dysphagia, or abdominal pain. After 2 hours in the emergency room, the patient was noted to have onset of spasm of the masseter muscles, as well as rigidity of the muscles of the anterior abdominal wall. Past medical history non-contributory.

Epidemiology: Born and raised in Moyobamba, high rainforested area of San Martin Department, where he works as a farmer. No known TB exposure or high-risk behaviors for HIV. No known animal bites. Unknown vaccination history.

Physical Examination: BP 120/90, HR 142, RR 32, T afebrile, SO2 95% (room air). Acutely ill appearance. Chest: clear to auscultation bilaterally. CV: tachycardic, no murmurs. Abdomen: distended, bowel sounds present, nontender no hepatosplenomegaly. Neurologic: Glasgow 15. Normal motor tone. No motor deficit, no meningeal signs. Muscle strength and deep tendon reflexes are preserved. Spasm of masseter muscles [Image A].

Laboratory Examination (on admission): Hct 39%. WBC 7.9 (no differential), platelets 280 000. INR 1.07. Glucose 166 mg/dL, BUN 20 mg/dL, creatinine 1.1 mg/dL. Normal electrolytes: Na 145 mEq/L, K 4.76 mEq/L, Cl 107 mEq/L, Ca 9.7 mEq/L, Mg 2.1 mEq/L. LDH 625 U/L (N<250), CPK 532 U/L (N < 170). sO2 99.8%, HCO3 18.5 mmol/L, lactate 0.9 mmol/L.

UPCH Case Editors: Carlos Seas, Clinical Course Coordinator/Sofia Zavala, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus
Diagnosis: Generalized Tetanus
Images for Case 2017-01
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Discussion: On detailed examination a wound of the left great toe was present [Image B] and the patient admitted to an accident 12 days earlier involving a dirty axe. Generalized tetanus is a purely clinical diagnosis with highly characteristic features, and, as in this case, the diagnosis is usually made within minutes of arrival at a medical facility. In general, disease begins with trismus or lockjaw, which are spasms of the masseter muscles, although, initial symptoms may occur in other muscle groups as in the patient where the neck muscles were initially involved. After a variable period, the symptoms progress to generalized muscular rigidity, on which is superimposed increasingly severe generalized reflex muscular spasms manifested by the characteristic sardonic smile (risus sardonicus), opisthotonos (arched back) [Images C,D], and spasm of respiratory muscles and larynx. See also previous cases ( 2011-10 2009-8). In severe cases there are prolonged spasms occurring less than 1 hour apart, and in very severe cases there is autonomic hyperactivity with sweating, fever, tachycardia, salivation, arrhythmias, hyper- or hypotension, hyperthermia, etc. Some aspects of generalized disease can be mimicked by hypocalcemic tetany, phenothiazine induced dystonia, epilepsy, rabies, strychnine poisoning, or narcotic withdrawal, but the history of wound (not elicited in up to 20%), epidemiology, and clinical course of tetanus usually lead to little confusion. Mild localized tetanus in which trismus does not progress to generalized disease with reflex spasms is rare. In the initial phase, the trismus itself has a broader differential diagnosis including dipththeria, parotitis, odontogenic abscess, peritonsillar abscess, retropharyngeal abscess, and traumatic injury, but in these cases trismus is due to pain and there is usually fever, whereas in tetanus trismus is due to masseter rigidity and initially there is no fever.

Disease is caused by a toxin, tetanospasmin, released by Clostridium tetani that infect the wound. Spread of toxin is both retrograde through the affected axons as well as via blood to nerve endings in other parts of the body. Masseters are usually affected first due to their short axons. The action is pre-synaptic, irreversible, and blocks inhibitory neurotransmitter action leading to muscle spasm. Poor prognostic indicators include short incubation period (< 7 days) from time of the wound to onset of symptoms (12 days here), short period of onset (?? 48 hours) from onset of symptoms to first reflex spasm, and high-risk portal of entry (compound fracture, gynecologic, postoperative, intramuscular injections, and burns).

Management is complex and must be done in a well-equipped Intensive Care Unit (ICU). Non-ICU care in severe cases is associated with high mortality. General principles are listed here, but detailed written dosing protocols must be available and used for most interventions.

1. Airway – in severe generalized tetanus, immediate endotracheal intubation to protect against laryngeal spasm is indicated. For those with poor prognostic signs, where even survivors will require weeks of intensive care while synapses regenerate, immediate or early tracheostomy is advised. Our patient was intubated two days after arrival due to difficulty controlling spasms and salivary secretions, and tracheostomy was performed one day later.

2. Relaxation-Sedation – must be titrated to eliminate reflex spasm. Large amounts of diazepam, up to 20 mg/kg/day by IV bolus combined with chlorpromazine have been used. Patients are relatively refractory to the sedating and respiratory depressive effects of diazepam. Midazolam is increasingly used and is standard in our hospital. A randomized controlled trial [Lancet. 2006 Oct 21;368(9545):1436-43-43] indicates that continuous magnesium sulphate infusion improves control of muscle spasms and autonomic instability and reduces the need for mechanical ventilation. Magnesium sulphate can be combined with diazepam to improve control. Artificial ventilation and complete neuromuscular blockade with vecuronium as the drug of choice is usually indicated.

3. Neutralize toxin – either human hyperimmune globulin (ideal) or equine anti-tetanus globulin should be given intramuscularly. Intrathecal immune globulin is of historic interest. A primary series of tetanus toxoid should be initiated, as disease does not protect against future infection.

4. Treat portal of entry – surgical debridement and antibiotics. Penicillin has classically been used but metronidazole is now used universally due to some data implicating penicillin as an antagonist of GABA [Ann Trop Med Parasitol. 2004 Jan;98(1):59-63-63], thereby decreasing benzodiazepine effectiveness.

5. General care – includes usual ICU considerations but also intense avoidance of light and stimuli as these readily precipitate reflex spasm.

6. Treat any sympathetic hyperactivity – among beta blockers, esmolol is preferred due to its short half life; combined alfa and beta blockade has also been used. Alternatively, morphine or clonidine with or without magnesium sulphate can be used.