Gorgas Case of the Week - 2018 Series

University of Alabama at Birmingham

Gorgas Case 2018-11

Universidad Peruana Cayetano Heredia
This is our last Case of the Week for 2018. We hope you have enjoyed the 2018 series of live cases each week from Peru. The Gorgas Diploma Course, in February and March, and the Gorgas Advanced course, in August, are held annually and we will be in touch at the beginning of next year’s case series.

Publishing these case reports would not be possible without the assistance of an extremely dedicated group of people. We would like to thank in particular UPCH Case Editor: Carlos Seas, UPCH Associate Coordinators: Karen Luhmann and Carlos McFarlane, UAB Case Editor: David O. Freedman, Course Director Emeritus, for case selection and coordination of case summaries and images, Dr. German Henostroza, UAB Course Director and Alfredo Guzman of the Gorgas Center for Geographic Medicine at the UAB Division of Infectious Diseases for all publishing on the Gorgas Course website.

The following patient was seen in the inpatient department of the 36-bed Tropical Disease Unit at Cayetano Heredia National Hospital in Lima-Peru.

Carlos Seas & German Henostroza
Course Directors
Image for Case 2018-11
History: 53 yo male with a 1 year history of profuse watery diarrhea (10 times per day) with nausea, vomiting and diffuse abdominal pain. He visited several private sector emergency rooms for intravenous rehydration and received short treatment courses of ciprofloxacin and TMP/SMX with only partial improvement. He lost 18 kg since the beginning of his illness. No cough, no fever, no night sweats. The patient was referred to our Institute for further evaluation.

Epidemiology: Born and lives in the Lima area where he works as street vendor. Currently married but over 15 total sexual partners including female sex workers. Alcohol abuse since age 14 yr. No known TB exposure. No relevant past medical history.

Physical Examination: BP 100/70, HR 73, RR 19, T 36.6°C, body weight 41 kg, BMI 16 kg/m2. Pale, no jaundice or rash. No lymphadenopathy. Chest and cardiovascular normal. Moderate abdominal pain to deep palpation in the right upper quadrant. Negative Murphy's sign. No visceromegaly, no peritoneal signs. Normal neurologic examination.

Laboratory Results and Imaging: Hb 12.4, WBC 6 300 (0 bands, 52 neutrophils, 2 eosinophils, 37 lymphs), platelets 446 000, creatinine 0.5 mg/dl, total protein 5.1 g/dl. albumin 2.3 g/dl. ALT/AST 111/113 UI/L (<40), alkaline phosphatase: 183U/L (<104). Serological tests for Hepatitis B, C, Syphilis and HIV were non-reactive.

Chest x-ray was normal
Abdominal ultrasound showed moderate hepatomegaly and chronic calculous cholecystitis.
Colonoscopy showed normal colonic mucosa.
Upper endoscopy showed superficial erosive gastritis in the fundus and gastric body.
A stool wet mount preparation is shown in Image A.

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: Chronic diarrhea due to Cystoisospora belli. HTLV-1 infection.
Images for Case 2018-11
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Discussion: Image B is a modified acid-fast stained stool showing a 10 μm x 20 μm oval oocyst of C. belli (long black arrow) containing two sporoblasts (two black arrows). C. belli can be diagnosed by observing these oocysts in, either, a stool wet-mount preparation or much better through a modified acid-fast or auraminerhodamine stain. Modified acid-fast staining is not regularly done when a request for stool O & P is made in most places. Therefore, it needs to be specifically thought of and ordered. Multiple samples using a stool concentration technique may be required for diagnosis. PCR is also available but usually not in developing countries. Stool culture was negative and no Strongyloides was found in several stool samples. In addition, HTLV-1 ELISA and Western blot tests were positive. On further questioning the patient disclosed that he had being diagnosed with cystoisosporiasis several months before and had been treated with short courses of antimicrobials with only partial response.

C. belli was identified as causing human disease during World War I. The genus previously named Isospora was recently reclassified, separating the species infecting birds from those infecting mammals, now termed Cystoisospora [Curr Opin Infect Dis. 2013;26:479]. This coccidian parasite has global distribution, with predominance in tropical and sub-tropical areas of the world. Transmission occurs by ingestion of contaminated food or by drinking contaminated water. Infections mainly occur in children in endemic areas, whereas outbreaks and point-source epidemics related to contamination of fresh produce occur in developed countries [Curr Opin Infect Dis. 2013;26:479]. C. belli should be included in the differential diagnosis of patients with persistent diarrhea, during waterborne or foodborne outbreaks, in travelers to endemic areas, and in immunocompromised patients.

C. belli infects both immunocompetent and immunosuppressed patients. The disease is usually mild in the former and it is characterized by fever, nausea and vomiting and watery diarrhea. Prolonged diarrhea with malabsorption and weight loss may also occur. Peripheral eosinophilia is a distinctive feature of this pathogen; no other coccidian parasites cause eosinophilia. Immunosuppressed patients present with more severe and prolonged diarrhea, and also may present with extra-intestinal manifestations. The parasite has been identified in samples from mesenteric lymph nodes, liver and from the spleen. Patients with advanced HIV-infection present with prolonged diarrhea are sometimes refractory to standard treatment [Rev Chilena Infectol. 2017;34:347]. Severely immunosuppressed HIV-infected patients and transplant patients may preset with gallbladder and biliary tract infection [Case Rep Infect Dis. 2018;2018:3170238]. C. belli and Cryptosporidium spp. should be included in the differential diagnosis in these settings. Patients with diarrhea who are found to have cystoisosporiasis should be immediately investigated for HIV and other immunocompromising conditions.

Immunosuppressive conditions associated with cystoisosporiasis include Hodgkin’s lymphoma, thymoma and acute leukemias. In a recent study in Brazil among cancer patients, C. belli was found in 4.4% of 73 patients [Braz J Biol. 2018;78:574]. There are few reports of C. belli in HTLV-1 infected patients. In one report, C. belli was found in the stools of an HIV negative patient with chronic diarrhea preceding the diagnosis of HTLV-1, as in our patient [Case Rep Infect Dis 2012; 640104]. HTLV-1 infection was documented and the patient developed adult T-cell leukemia lymphoma and died. In another report, a patient with adult T-cell lymphoma associated with HTLV-1 presented recurrent C. belli infection and co-infection with C. difficile [ID Cases 2017;10:122]. Another report document the case of an Iranian women with severe diarrhea and weight loss [Iran J Parasitol 2016;11:121]

In Peru, HTLV-1 is highly endemic (2-3% prevalence) in Andean areas of the country in Quechua populations who have had no contact with Japanese immigrants to the country. Other South American countries with significant rates of HTLV-1 include Brazil, Colombia, and Ecuador. We have seen over 800 infected families to date at the Tropical Medicine Institute in Lima. Disseminated strongyloidiasis is the most common and severe intestinal parasitic complication [see Gorgas Cases 2007-4; 2010-10; 2012-3], but a number of other conditions are associated with HTLV-1 infection; [see Lancet Infect Dis. 2007 Apr;7(4):266-81 for a detailed discussion]. Crusted (Norwegian) scabies [see also Gorgas Case 2008 #8] : tropical spastic paraparesis (TSP), also called HAM (HTLV-1 associated myelopathy) [see Gorgas Case 2002 #8], infective dermatitis [see Gorgas Case 2004 #7], adult T-cell leukemia/lymphoma (ATLL) [see Gorgas Case 2009 #11], autoimmune disease including uveitis, Sjögrens, arthropathy, polymyositis, and thyroiditis. Associations with bronchiectasis (Clin Infect Dis. 2012 Jan;54(1):43-50) and paracoccidiodomycosis Clin Infect Dis. 2010 Jul 15;51(2):250-1 are recently described. This patient did not have any neurological findings. More than 90% of individuals with HTLV-1 infection remain asymptomatic for life. Worldwide, approximately 0.3-4.0% develop TSP and 1-5% develop ATLL. Although the pathogenetic mechanisms of these two major complications likely differ, the low rates of each means that it is rare to see both sequelae in the same patient.

There is limited experience with the treatment of C. belli in patients with immunosuppressive conditions other than HIV. TMP/SMX is the drug of choice; the double strength preparation twice-daily for 7-10 days is the drug and regimen of choice. The oral route is preferred, but the intravenous route in patients with poor oral tolerance is advised [N Engl J Med 1986;315:87]. Oral suppressive therapy is recommended in HIV infected patients due to the high relapse rate, but no good information is available in other immunosuppressive conditions. Alternative agents with less efficacy than TMP/SMX include ciprofloxacin, nitazoxanide and pyrimethamine. Our patient was treated with a 10-day course of TMP/SMX with resolution of symptoms.

University of Alabama at Birmingham

Gorgas Case 2018-10

Universidad Peruana Cayetano Heredia

The following patient was seen in the outpatient department of the Tropical Disease at Cayetano Heredia Hospital in Lima, Peru during the Gorgas Advanced Course. 

Image for Case 2018-10
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History:  A 56-year-old female presented with a 2-month history of progressive swelling of the left malar, periorbital, and upper lip areas associated with the appearance of multiple non-painful nodular lesions. The patient reports swelling and erythema of these areas (Image A) with no fever or constitutional symptoms beginning 1 week after a cosmetic procedure whereby fat from her abdomen was injected into both cheeks. She subsequently received 30 days of multiple sequential antibiotics including clindamycin, intramuscular ceftriaxone, amoxicillin/clavulanate and steroids with resolution of the swelling over the malar and periorbital regions but with the appearance of multiple painless nodular lesions ranging from 0.5 cm to 1 cm in diameter in the malar and upper lip regions. Over the next month, the nodular lesions evolved into abscesses which were drained. Culture for usual bacteria and Ziehl-Neelsen staining were negative and she was referred to our institution for further evaluation.

Epidemiology:  Born and resides in Lima. Recent travel to San Andres island, Colombia as well as Huancayo and Ancash in the Peruvian highlands over the last year for tourism. No known TB contact. She has had hypothyroidism for 26 years in treatment with levothyroxine.

Physical Examination:  BP: 120/80 mmHg. HR: 74 bpm. RR: 18 rpm. Afebrile. Skin: multiple abscesses located on the left malar region, left upper lip and right malar region over an edematous and erythematous base with skin retraction on the left suborbital area (Image B). No lymphadenopathy, no oral or intranasal lesions. Normal chest cardiovascular and abdominal examination.

Laboratory Results and Imaging: Hct: 43.8%; WBC 11,700 (78 neutrophils, 15 lymphs, 5 monos); 379,000 platelets INR: 1.17; total protein 6.66 g/dl (N 5.8-8.1); albumin 3.69 g/dl (normal); globulin 2.97 (N 2-3.5); total bilirubin: 0.25mg/dl; ALT 17 U/L (N=< 40); AST 15 U/L (N=<40); Alk phosphatase 45 mg/dl (N 15-60). HIV and HTLV-1 tests were non-reactive.

Ultrasound: signs of left facial cellulitis with presence of subcutaneous abscesses, the larger located in the left malar region with presence of a cutaneous fistula.

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: Mycobacterium chelonae. Iatrogenic subcutaneous infection.
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An abscess was drained and a non-tuberculous mycobacterium was isolated within a week on solid media. PCR testing was positive Mycobacterium chelonae. Drug susceptibility testing disclosed resistance to cefoxitin, doxycycline, imipenem, linezolid, minocycline, moxifloxacin and TMP/SMX, and susceptibility to amikacin, tobramycin and clarithromycin.

With an increase in cosmetic procedures (mesotherapy, liposuction, fat autografting, and breast augmentation), skin and soft tissue infections caused by rapidly growing mycobacteria (RGM) are increasing in incidence (Aesth Plast Surg 2017;41:1150–1154; Clin Infect Dis 2009; 49:1358–64). "Lipotourism" to Latin America has been associated with RGM outbreaks in returning travelers to the US and Europe <https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6309a5.htm>. Common source outbreaks have also been reported after acupuncture, insulin injections, tattooing procedures (N Engl J Med 2012;367:1020-4), and potentially with any procedure that involves injectable materials, artificial prostheses, central venous catheters and implantable devices. Mesotherapy has become a popular procedure in Latin America despite of lack of scientific evidence for its utility (Rev Saúde Pública 2008;42:146-9). Mesotherapy involves injecting various substances into the dermis that supposedly eliminates fat tissue in an attempt to contour the body. Fat injection procedures are also becoming popular as they are considered safer and associated with better esthetic results (Plast Reconstr Surg 2011;128:545–555). Contamination of substances injected during mesotherapy and of tattoo ink are more implicated than the procedures themselves (Rev Saúde Pública 2008;42:146-9; N Engl J Med 2012;367:1020-4).

Mycobacterium chelonae is a nontuberculous, Runyon type IV mycobacterium found in water, soil, plants, dairy products, and cold-blooded animals. In humans, it is usually seen in immunosuppressed patients, presenting with disseminated infection. However, after skin inoculation infection often presents with induration, edema, erythema, draining subcutaneous nodules, abscesses, and also with constitutional symptoms. For instance, a Peruvian report indicates that during a period of two months, 35 patients underwent mesotherapy at a local private clinic, all of them developed skin lesions,13 patients were evaluated at our Institution. In these 13 patients, the mean incubation period was 16 days; fever was reported in 40%; sub cutaneous nodules and abscesses were reported in 92% of them, 8% presented with skin ulcers; M. chelonae was isolated form 4 patients and from a procaine vial used during the procedures (Rev Saúde Pública 2008;42:146-9).

Our patient presented with inflammatory manifestations very quickly after the procedure, early infections by M. chelonae have been reported even within one week but usually occur several weeks of the esthetic procedure. However, in this case we cannot rule out a cellulitis caused by common bacteria that resolved with antibiotics which was then followed one month later by the classical manifestations of subcutaneous infections caused by RGM.

Diagnosis is complicated and often delayed and requires a high index of suspicion and close collaboration with the microbiology laboratory. M. chelonae, M. fortuitum and M. abscessus are RGM. These RGM have the ability to grow usually within one week on solid medium. Drug susceptibility tests (DST) are performed at reference laboratories; clinicians often claim that no direct correlation between susceptibility results and clinical efficacy is observed. DST to aminoglycosides, fluoroquinolones, clarithromycin, azithromycin, linezolid, imipenem, doxycycline, cefoxitin, trimethoprim-sulfamethoxazol and tigecycline is recommended.

Unfortunately, no evidence-based data exist from randomized controlled trials to guide the proper therapy. M. chelonae is often fully resistant to first line anti tuberculous medications. Expert recommendations for limited soft tissue infections are for at least four months of treatment with two oral agents to which the cultured isolate is susceptible, but for more severe soft tissue infections parenteral therapy with two agents based on culture susceptibility results are suggested (J Infect Dis. 1985;152:500; Ann Intern Med 1993;119:482). Once the patient clinically improves, switching to oral therapy with two medications for a total of six to twelve months is advised. Multiple surgical debridements are always needed to reduce the burden of infection.

The treatment recommendations at our center for this kind of infections include 3-drug therapy with an aminoglycoside (we prefer amikacin) until there is clinical improvement and two oral agents that usually include a quinolone and clarithromycin for at least 6 months. This patient was started empirically with amikacin 15mg/kg per day for 10 days, and levofloxacin 750 mg PO qd plus clarithromycin 500mg PO bid that she received for 6 months with continuous aspiration of the skin abscesses. The patient improved significantly as seen in Image C, taken after 6 months of treatment. Tobramycin, which has the highest in vitro activity against M. chelonae, is not available in Peru; the strain from our patient was susceptible to amikacin. Despite in vitro quinolone resistance, the patient was improving clinically when the DST results became available and the strain was resistant to the other drug classes as well.

University of Alabama at Birmingham

Gorgas Case 2018-09

Universidad Peruana Cayetano Heredia

The Gorgas Course in Clinical Tropical Medicine 2018 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 on the inpatient service of the Regional Hospital of Loreto.

Image for Case 2018-09

History:  30-yo-male, admitted with a 4-day history of fever, chills, myalgia, progressive dyspnea and jaundice. Initial symptoms were myalgia, predominately in the calves, chills, weakness and fever. Three days later the muscle pain was severe enough to prevent walking, fever persisted and dyspnea increased. Jaundice was noticed on admission. He denies any abdominal pain or diarrhea.

PMH: 4 years ago, classic dengue with outpatient treatment.  Surgery to arm 10 years earlier after trauma.

Epidemiology:  Born and lives in Iquitos, works as a welder. No history of routine vaccines or against yellow fever, or hepatitis B.  No history of malaria, TB, known TB contact, intravenous drugs, or high-risk sexual activity.  He lives near a river and consumes non-potable water from the river. He also swims in a pond near his house. There is no history of recent flooding.

Physical Examination:  T: 37.9°C, HR: 105bpm, RR: 32/min, BP: 100/60mmHg, Sat: 95% on Venturi Mask with 15L Oxygen. Acutely ill patient with marked jaundice in both skin and sclera (Image A). No Rash. No lymphadenopathy. Chest: Rales were present in both lungs; predominantly in the bases.  Abdominal: Mild pain and tenderness with deep palpations and no hepatosplenomegaly. Cardiovascular: Normal heart sounds, no murmurs. Glasgow scale 15/15 on admission.

Laboratory Examination and Imaging:  Hct: 28%; Hb 11.6 g/dl; WBC 8,200 (84 neutrophils, 7 lymphs, 8  monos); 39,000 platelets INR: 1.17; creatinine 2.71 mg/dl (N=<1.2); urea: 80 mg/dl (N=<45); Glucose: 140 mg/dl; total protein 5.74 g/dl (N 6.6-8.3); albumin 3.51 g/dl (normal); Total bilirubin: 10.6 mg/dl (N=<1.2), 6.37 mg/dl direct.  ALT 75 U/L (N=< 33); AST 107 U/L (N=<35); Alk phosphatase 614 mg/dl (N=<270); Chest x-ray: Extensive diffuse alveolar and interstitial infiltrates bilaterally. (Image B)

UPCH Case Editors: Carlos Seas, Course  Director / Karen Luhmann, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis:  Weil´s Syndrome (Severe Leptospirosis)

Discussion: Positive IgM for leptospirosis; the test used has a reported sensitivity of 84% and specificity of 91% for the diagnosis of acute leptospirosis [Cien Saude Colet 2017;22:4001]. Negative malaria smear. Negative HIV and Hepatitis B serology. Positive IgM for dengue with negative NS1 antigen, both taken the day of admission. The positive IgM for dengue with a negative NS1 antigen taken before seven days of illness makes the diagnosis of acute dengue less likely in this case. In addition, liver compromise with transaminitis in dengue is common, but the constellation of symptoms and signs, in particular the presence of muscle pain, the development of significant jaundice with relatively normal liver transaminases, acute renal failure and pulmonary involvement is most highly suggestive of leptospirosis. Serology by the Microagglutination technique (MAT) for leptospirosis, which is considered the gold standard for diagnosis was not available at the Hospital.

Leptospirosis needs to be considered in the differential diagnosis of any undifferentiated tropical fever.  It has protean clinical manifestations and at differing stages of the illness may be impossible to distinguish clinically from yellow fever, dengue, rickettsial disease, typhoid, malaria, brucellosis, tuberculosis, or viral hepatitis.

Typically, leptospirosis is described as having an initial septicemic phase, which may be mild, with fever, myalgia, headache, conjunctival suffusion (see Gorgas Case 2008-04 and Gorgas Case 2009-04), and abdominal wall pain.  Our patient had the typical muscle tenderness in calves often described as distinguishing features of leptospirosis and marked jaundice, but did not present with conjunctival suffusion.  The illness is often self-limited but in some cases, after an apparent recovery, may present a biphasic illness and progress to an immune stage manifest by fever, meningitis, and uveitis.  The two distinct stages may be obscured and run together in severe disease (Weil’s Disease) manifested by the classic defining triad of jaundice, hemorrhage, and renal failure.  Weil´s disease has a mortality of 10%.

The true incidence of pulmonary involvement is unclear, appears to have increased in recent years, and may be as high as 70%.  Patients may present with symptoms ranging from cough, dyspnea and hemoptysis to ARDS [Respirology 2018;23:28 and Clin Infect Dis. 2005 Feb 1;40(3):343-51].  The present case shows a typical radiographic evolution that is thought to represent intra-alveolar and interstitial hemorrhage [Braz J Infect Dis. 2007 Feb;11(1):142-8].  Pulmonary involvement has emerged as the main cause of death due to leptospirosis in some countries.

Jaundice and bilirubinemia out of proportion with hepatocellular damage is the usual finding in leptospirosis.  This is manifest as significant jaundice in the face of an SGOT and SGPT that is no more than 3-4X normal with an alkaline phosphatase that may be as high as 10X normal.  The mechanism of the cholestasis in leptospirosis is not entirely clear.  In severe or prolonged disease, renal damage will occur and the sediment is usually active.  Non-oliguric hypokalemic renal failure is characteristic.  Progression to oliguric renal failure would be predictive of higher mortality. More recently, neutrophil and platelet counts have been identified as predictors of mortality [Trans R Soc Trop Med Hyg 2017;111:531].

Isolation of Leptospira in culture is difficult and insensitive. Culture in special media in tubes held at 28-30°C for prolonged periods is necessary.  Blood is only positive in the first week of illness after which urine becomes progressively more positive.  Cultured leptospires are only visible and confirmed using dark-field microscopy.  Diagnosis is most often serological and retrospective [MAT], IgM ELISA, or a commercially available rapid dipstick test.

Leptospirosis is endemic in almost every country but more so in the tropics. The incidence of leptospirosis in the Americas is difficult to determine. A survey of 24 countries performed between 1996-2005 showed that Brazil (3165 annual cases) and Cuba (558 annual cases) had the highest burden of disease [Rev Panam Salud Publica 2012;32:169]. Peru reported approximately 100 cases annually during that study period. Traditionally an occupational disease and a disease of poverty in peri-urban slums, it has also emerged as a disease of adventure travelers (hikers, bikers, boaters, swimmers) that have contact with standing or moving water. Leptospires may penetrate conjunctiva, macerated skin, or possibly the oropharynx.  Leptospirosis is maintained in the environment by long-term carriage and excretion of the organism from the urinary system of asymptomatic animal carriers.  Rodents are most frequently implicated with swine, cattle, and dogs next most frequent, but the full spectrum of mammals forming the reservoir is unclear. Our patient told us that he has seen rodents inside his house and that he uses to swim in a pond near his house.

Classification of leptospires is complex and obscure to most clinicians.  While most human isolates are L. interrogans, further division into a number of species using DNA relatedness is hampered by a traditional naming system that uses serologically defined antigenic determinants (serovars and serogroups) that may be shared by two or more species.

Clinical trials support the use of intravenous antibiotics for severe disease.  Cefotaxime or ceftriaxone are equivalent to penicillin and much more convenient due to once daily dosing [Clin Infect Dis. 2003;36(12):1507-13.Clin Infect Dis. 2004;39(10):1417-24.].  Milder disease may be treated with oral doxycycline.  Efficacy appears best when treatment is begun within 4 days of illness onset.

The patient deteriorated over the first day in the hospital after several episodes of hemoptysis progressing to marked respiratory distress for which he required intubation and mechanical ventilation in the ICU. Renal function normalized by day 5 after three sessions of hemodialysis. He was treated with IV ceftriaxone 1g/d for 10 days with full recovery but some residual jaundice at discharge. He will be followed by our colleagues at the Regional Hospital.

University of Alabama at Birmingham

Gorgas Case 2018-08

Universidad Peruana Cayetano Heredia

The following patient was seen in the Outpatient Department of the Hospital Cayetano Heredia.

Image for Case 2018-08
History: 41yo previously healthy female, presents with an 8-month history of oppressive right upper quadrant pain (up to 7/10), which is intermittent, without radiation, and associated with nausea and episodic diarrhea without mucus or blood. The pain has increased in the last two months and now radiates to the back with exacerbation with food intake with resulting anorexia. No fever, rash, jaundice, vomiting, or joint pain.

Epidemiology: Born and lives in Huaraz, in the Peruvian highlands. Non-smoker, no alcohol abuse, no known TB exposures. No HIV risk factors. Normal diet with ingestion of lettuce, spinach and other vegetables. Occasional contact with Guinea pigs. Denies any travels for the past year.

Physical Examination on Admission: BP: 110/60mmHg.  HR: 70. RR 19. Weight 55kg. Height 1.46m. Afebrile with no lymphadenopathy. Skin: No jaundice or rash. Chest: Clear. Abdomen: Mild tenderness and pain to deep palpation in the right upper quadrant and a liver span approx. 14cm with a palpable edge. Negative Murphy's sign. No splenomegaly. Rectal exam is normal.

Laboratory Examination and Imaging:  WBC 9 110 (0 bands, 31% segmented neutrophils, 35 eosinophils, 7 monos, 27 lymphs). Hb 14.2g/dl, Hct 40%. Platelets 321 000. Glucose 95 mg/dl. Urea 27 mg/dl. Creatinine 0.4 mg/dl. Total protein 6.9 g/dl. Albumin 3.3 g/dl. Total Bilirubin 0.5 mg/dl. ALT/AST 38/57 UI/L. Gamma-glutamyltransferase 104 UI/L. Alkaline phosphatase: 274U/L (N<104). Serological tests for Hepatitis B and C, HTLV-1 and HIV were negative. Abdominal CT-Scan is shown in Image A.

UPCH Case Editors: Carlos Seas, Course  Director / Karen Luhmann, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis:  Fasciola hepatica infection
Images for Case 2018-08
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Discussion: IgG Fas2-ELISA for Fasciola hepatica was positive at UPCH, a stool sample was positive for eggs of Fasciola hepatica (Image B).  The abdominal CT scan (Image A1) shows ill-defined areas of low attenuation (blue arrow), and tunnel-like branching hypodense areas (red arrow) inside the liver. The rounded lesions are non-specific and cannot be distinguished from neoplasms or either pyogenic or amebic liver abscesses, the presence of tortuous channels make fascioliasis the leading diagnosis. Hepatic calcifications as a sequelae of massive hepatic infestation have been reported (See Gorgas Case 2005-02).

The differential diagnosis of eosinophilia with accompanying destructive hepatic lesions is very limited. Toxocariasis causes hypereosinophilia with hepatomegaly but it is more common in children, acute schistosomiasis is another option, but is not endemic in Peru. Amebic liver abscess tends to be a single lesion and is not associated with eosinophilia. Recent advances in the diagnosis of chronic infection using molecular methods on stool samples show potential benefit for implementation in developing countries [Am J Trop Med Hyg 2017;96:341].

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 or alfalfa. Recent data, however, also suggests waterborne transmission. Our patient denies ingestion of watercress or alfalfa, but did admit to eating salads with lettuce. 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 into adults.

The mature adults are from 1 to 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.

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 contiguous 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]. Fascioliasis has been also found in the jungle of Peru [Am J Trop Med Hyg 2015;94:1309]. 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. 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 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. Malignant degeneration and cholangiocarcinoma such as results from chronic infection with the oriental liver fluke Clonorchis sinensis has not been reported with F. hepatica. However, liver fibrosis and liver cirrhosis have been reported with chronic Fasciola infection [Plos Negl Trop Dis 2016;10:e0004962]. We have reported a case series with clinical findings and evolution of disease [Am J Trop Med Hyg. 2008 Feb;78(2):222-7]. Please see Gorgas Case 2005-02 and Gorgas Case 2015-05 for CT images of other examples with the typical larval tracks seen in acute disease.

Fasciola hepatica is the only trematode infection for which praziquantel is not the drug of choice. 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. In the U.S. the drug is available from the CDC Parasitic Drug Service. The usual dosage is 10 mg/kg with a meal. Many practitioners repeat the dosage 12 to 24 hours later. In initial studies at our institute, the cure rate was 96%, but it has been lower in recent experience suggesting resistance to triclabendazole [PloS Negl Trop Dis 2016;10:e0004361].

Treatment with triclabendazole 10 mg/kg in a single dose was provided to the patient with resolution of her symptoms within one week. An abdominal CT scan taken almost two years after finishing treatment shows complete resolution of the tract lesions in the liver (Image C).

We would like to thank Dr. Eduardo Gotuzzo for presenting this case.

University of Alabama at Birmingham

Gorgas Case 2018-07

Universidad Peruana Cayetano Heredia

The following patient was seen in the outpatient department of the Tropical Disease at Cayetano Heredia Hospital in Lima, Peru.

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History: An otherwise healthy, 68-year-old male presented with a 25-year history of slowly progressive verrucous lesions of the left lower limb. The initial lesion was a pink smooth-surfaced papule on the left shin, that increased in size over a few weeks and became painful. Slow progression occurred over the next 1 ½ years to involve the whole left lower limb (including the foot) with polymorphic lesions including verrucous plaques, nodules and scars. The lesions became and remain pruritic and gradually became painless. No drainage, purulence or granular material was noticed by the patient at any time. Various treatments including oral antibiotics, local therapy, and topical herbs have had no effect. The patient denies fever, other skin lesions, constitutional symptoms or history of any specific trauma. Functionality of the left leg is moderately affected but the patient still works.

Epidemiology: Born and still resides in Pucallpa, in the Amazonian jungle. Rice and corn farmer; also carries and sells wood. Contact with chickens, cows, dogs, and cats. Walks by rivers, and is often bare footed.  No known TB contact.

Physical Examination on Admission: BP: 120/80 mmHg. HR: 74 bpm. RR: 18 rpm. Afebrile. Sat: 98 % (FiO2: 0.21). Skin: Diffuse and extensive lesions of the left lower limb, with multiple erythematous nodules and slightly elevated plaques. The lesions are markedly hyperkeratotic, dry looking, verrucous with central atrophic scarring, some of them present black dots (upper panel) and no suppuration (Image A). There is no lymphedema, sinus tracts, synovitis, joint effusions or restricted range of motion of joints. No lesions were found elsewhere. Rest of the physical exam is unremarkable including the neurologic examination.

Laboratory Examination and Imaging: WBC 8.2 (0% bands, 58% segmented, 15% eosinophils, 4% monos, 22% lymphs). Hb 13.3g/dl, Hct 40%. Platelets 331 000. Glucose 92 mg/dl. Urea 37 mg/dl. Creatinine 0.9 mg/dl. Total protein 7.9 g/dl (Normal). Albumin 4.3 g/dl. Left lower limb X-Ray showed tenuous nodular opacities in the soft tissues with obliteration of the superficial and deep fascial planes in the leg and right foot (Image B), no radiographic abnormalities in the bone structures. Serological tests for Hepatitis B, HTLV-1 and HIV were negative. Repeated stool samples showed cysts of Entamoeba coli and eggs of Ascaris lumbricoides.

Superficial skin scrapings, focusing on areas with black dots also known as "cayenne pepper" were obtained for diagnosis (See video)

UPCH Case Editors: Carlos Seas, Course  Director / Karen Luhmann, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Chromoblastomycosis likely due to Fonsecae pedrosoi.
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Discussion: Chromoblastomycosis was confirmed through the detection of pathognomonic muriform cells with a potassium hydroxide (KOH) preparation (Image C) of the superficial skin scrapings which had intentionally focused on the areas with black dots as this may increase the likelihood of detecting fungal elements (See video). Muriform cells are double-walled yellow-brown structures with a diameter of 4 to 10 microns that resemble copper pennies. Thick and dark hyphae are sometimes identified (Image D). Fungal culture in Sabouroud´s Agar, grew a dematiaceous black fungus (Image E) compatible with Fonsecae pedrosoi by recognition of the conidiophore micromorphology. Confirmation of the pathogen by PCR is pending.

Chromoblastomycosis is considered the second most common soil transmitted or inoculation mycoses in the world after Sporotrichosis [Lancet Infect Dis 2017;17:e367] and it is clinically restricted to sub-cutaneous tissues. The disease occurs mostly among farmers through skin inoculation after trauma.

Chromoblastomycosis occurs worldwide, including in the USA, but 70% of cases are estimated to occur in the moist tropics. Most cases in Latin America are from the humid Amazon 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 reported from Madagascar and South Africa. Up to 90% of cases occur in males likely due to occupational factors. Incidence rates in Madagascar have been estimated in 1 per 6800 inhabitants.

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:

  1. 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), Exophiala sp. and Pyrenochaeta sp., as well as Fusarium and Acremonium(produce pale granules).
  2. 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 ExophialajeanselmeiWangiella dermatitidis, and Bipolarisspecies. Hyphae are typically seen histologically.
  3. 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. Sclerotic bodies or also known as muriform cells 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 environments) and Cladophialophora carrionii (drier environments), with Phialophora verrucosa, and Rhinocladiella aquaspersa being less common. Clinical forms of the disease may be associated with cytokine response with tumor necrosis factor and interleukin 10 being reported in severe cases [Clin Microbiol Rev 2017;30:233].

The differential diagnosis of a life-long subcutaneous indolent infection like this includes: sporotrichosis [Gorgas Case 2008-01], eumycetoma [Gorgas Case 2002-04] (no drainage with grains were reported in this case), actinomycetoma [Gorgas Case 2001-09], lobomycosis (lacaziosis) [Gorgas Case 2005-03], subcutaneous zygomycosis, subcutaneous phaeohyphomycosis, botryomycosis [Gorgas Case 2003-04], leishmaniasis [Gorgas Case 2004-01], nocardiosis [Gorgas Case 2011-01], and tuberculosis verrucosa cutis. Squamous cell carcinoma and leprosy are less likely.

Treatment of chromoblastomycosis is often difficult and is based on case reports and case series; there are no controlled trials [Lancet Infect Dis 2017;17:e367]. Surgical excision of early lesions is recommended. Treatment choices include itraconazole alone or in combination with terbinafine (expensive and not typically available in the tropics). With very chronic infection like this, itraconazole may induce significant 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.

Of the newer azoles, voriconazole has potent in vitro activity against Cladophialophora carrioniiF. pedrosoi, and P. verrucosa; posaconazole is approved in Europe for refractory chromoblastomycosis; and caspofungin has potent in vitro activity against F. pedrosoi [Med Mycol. 2011 Apr;49(3):225-36].

Our patient was started on itraconazole but presented marked oral intolerance with severe nausea and vomiting and was switched to terbinafine 500 mg per day. After two weeks of treatment, he mentioned some flattening of old lesions. The planned duration of treatment in this patient is no less than 1 year.


We would like to thank Dr. Beatriz Bustamante and the Mycology Laboratory for assistance with the diagnostic workup.
University of Alabama at Birmingham

Gorgas Case 2018-06

Universidad Peruana Cayetano Heredia

The following case was seen on the inpatient ward of Cayetano Heredia Hospital in Lima by the 2018 Gorgas Course participants.

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History: 45-year-old man was admitted with a 5-day history of generalized headache (6/10 intensity), body aches, and fever characterized as a very intense cold sensation with chills and rigors evolving into sweats and an intense hot feeling.  Febrile episodes were continuous during the 5 days of the current illness. The day of admission the patient reports rigors, jaundice and onset of dark urine (Image A and B).  Denies rash, arthralgia, mental status changes, bruising, bleeding or visual symptoms.

Past Medical History: Hospitalized 8 weeks earlier, in Iquitos in the Amazon region, for smear positive Plasmodium vivax for four days and treated with directly observed chloroquine base 600mg/day for 2 days and 300mg on the third day and primaquine 30 mg/day for 7 days. He returned to Lima for the final days of primaquine treatment. Ten years ago, he had malaria due to Plasmodium falciparum treated with artesunate 250mg/day for three days and mefloquine 750 mg/day for days 2 and 3 per the national protocol for P. falciparum.

Epidemiology: Born and lived in Iquitos but moved to Lima 3 years ago. Traveled to Iquitos 27 days before the first hospitalization and stayed on a farm 8-hours by boat from the city. Denies any travel back to Iquitos since. No known TB contacts. Currently, there are cases of dengue, chikungunya, Zika, and leptospirosis in the region.

Physical Examination on Admission: Patient presented to the ER, with normal mental status and in no apparent distress.

BP: 110/70 mmHg. HR: 79 bpm. RR: 20 rpm. T: 37o C. Sat: 98 % (FiO2: 0.21)

Skin: scleral icterus. Chest: clear to auscultation bilaterally, no crackles. Cardiovascular: regular heartbeat, no murmurs. Abdomen: soft, non-distended, normal bowel sounds heard, not tender to palpation; palpable tip of the spleen, no hepatomegaly. Neurological exam was normal.

Laboratory Examination and Imaging: WBC 4.7 (3% bands, 48% segmented, 1% eosinophils, 4% monos, 43% lymphs). Hb 11.2g/dl, Hct 34%. Platelets 90 000. Glucose 119 mg/dl. Urea 19.2 mg/dl. Creatinine 1.02 mg/dl. Sodium 146mEq/L. Potassium 3.71mEq/L. Chloride 110 mEq/L. Total Bilirubin 3.93mg/dl. Direct Bilirubin 2.48mg/dl. ALT/AST 59/44UI/L. Gamma-glutamyltransferase 312UI/L. INR 0.98. TP 12.8. TTP 33.7. Abdominal ultrasound showed no hepatosplenomegaly. Chest x-ray: normal

UPCH Case Editors: Carlos Seas, Course  Director / Karen Luhmann, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Relapse of Plasmodium vivax malaria.
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Discussion: Thick film on admission showed P. vivax ++; schizonts that were easily seen throughout the smear (Image C) as well as P. vivax gametocytes.  P. vivax characteristically shows parasitized red blood cells that are larger than non-parasitized ones and the membrane shows caveolae that take up the stain and appear as pink granules called Schüffner dots. Schizonts of P.vivax typically have 12-24 nuclei which will eventually be released as merozoites upon maturation and lysis of the red blood cell to infect new red blood cells.  Gametocytes are the only life-cycle state that develop further after being ingested by mosquitoes. Macrogametocytes (female) of P. vivax are round to oval, have a compact nucleus and usually fill the host cell (Image D).   Microgametocytes (male)  (not shown here) are usually the size of an uninfected RBC and have a paler blue, pink or gray cytoplasm and a loose nucleus. Other forms seen in P. vivax are ring (Image E) and ameboid trophozoites (Image F).

In cases of falciparum malaria only ring trophozoites +/- banana shaped gametocytes are seen in the peripheral blood, the other parasite stages are not seen because the parasitized RBC attaches to the endothelial cells in visceral capillaries and do not circulate in peripheral blood, except in severe infections where schizonts may be seen. The banana-shaped gametocytes are unique to P. falciparum and were not seen in this patient. The malaria parasite density is assessed under microscopic examination after reviewing 100 fields. A qualitative method for description is often used in Peru, where 2+ is defined when 2 - 20 parasites are seen per field in 100 fields, as in this case.

The differential diagnosis in this case will include bacterial infections like typhoid fever, brucellosis or tuberculosis, but these diseases usually do not start with chills and rigors.  Other possibilities could include viral hepatitis or a liver abscess, and other viral illnesses like dengue, Zika or chikungunya, but the incubation period of these latter diseases is usually not longer than two weeks. Leptospirosis is common in the jungle; however, the incubation period is shorter compared to this case, and the fever tends to have a biphasic presentation where it resolves for 1-3 days and then reappears. It is usually accompanied by myalgia, conjunctival suffusion and renal failure. In a febrile patient that has visited a malaria endemic area, malaria should be the first diagnosis until proven otherwise. Characteristically in malaria there is no leukocytosis, except in severe malaria, and there is usually anemia and thrombocytopenia, as in this case. Jaundice is also very common.

Malaria is endemic in Peru, the overall incidence rate in 2017 was 0.03 per 1000 inhabitants. The Loreto Department concentrates 93% of the total number of cases with an incidence rate of 0.87 per 1000 habitants; 73% of these cases were due to P. vivax [Centro Nacional de Epidemiologia, Prevención y Control de Enfermedades, Ministerio de Salud, Peru, 2017].

Relapses are important contributors to illness and morbidity in Plasmodium vivax and P. ovale infections. Relapse prevention (radical cure) with primaquine is required for optimal management, control and ultimately elimination of Plasmodium vivax malaria. However, its use is problematic because of uncertainty, over the risks of primaquine induced hemolysis due to G6PD deficiency, that is why this should be tested before starting treatment. In Peru, and at least also in Brazil, G6PD deficiency is so rare [Mem Inst Oswaldo Cruz, Rio de Janeiro 2014; 109(5): 553-568] that testing is not routinely done or required by national policy, and that is why primaquine is freely administered without complications.

On his initial presentation in Iquitos, this patient received 30mg per day of primaquine base to complete a total dose of 210mg over 7 days. Assuring proper elimination of hypnozoites depends on the total cumulative dose more than on the duration of treatment or the dosing schedule. The World Health Organization (WHO) recommends a total dose of 210mg (0.25 mg/Kg of primaquine base/day/14 days) [Malaria Journal 2011; 10:351-62], and the Centers for Disease Control and Prevention (CDC) recommends a total dose of 420mg (0.5 mg/Kg of primaquine base/day/14 days) [JAMA 2007; 297(20):2264-77]. In Oceania and Southeast Asia, the effective dose to kill hypnozoites is 420mg [Antimicrob Agents Chemother 2012; 56(4):2146-9]. The total dose should ideally be 6mg/Kg of weight [Am J Trop Med Hyg 1977; 26(3):562-3]. Accordingly, in this case, this patient weighed 70kg, so he should have received 420mg which likely accounts for his relapse.

Other possible reasons to explain P. vivax relapses such as this, in addition to low cumulative dose of primaquine, is lack of compliance with treatment, which was not the case with this patient; use of poor quality antimalarial drugs [Malaria J 2016;15:302], or drug malabsorption, which was not proven in this case.

This patient was treated after he arrived at our hospital with 4 doses of intravenous artesunate, while P. falciparum was being ruled out because of concern for severe P. vivax malaria in a jaundiced patient.  After P. falciparum was excluded he received chloroquine base 600mg/day for 2 days and 300mg on the third day and primaquine 30 mg/day for 14 days. Fever resolved after 2 days of treatment and the smear cleared after 3 days.

Criteria for severe malaria due to P. vivax, according to the latest WHO manual, are the same as for P. falciparum but do not include parasite density thresholds [Guidelines for the treatment of malaria, third edition, World Health Organization 2015]. Jaundice in P. vivax malaria is very common, and it is considered one criteria for severe malaria based on the guidelines. However, in clinical practice, these patients respond well to standard oral medications and do not need to be treated as severe cases. Therefore, some malaria experts believe that criteria for severe malaria in vivax or other non-falciparum species should be reviewed.

We would like to thank Dr. Pedro Legua for his contribution in the discussion of this case.
University of Alabama at Birmingham

Gorgas Case 2018-05

Universidad Peruana Cayetano Heredia
This past week, the annual field trip to Cuzco in the Andean highlands took place. Cusco (elevation 3400m) is the oldest continuously inhabited city in the Americas. The patient was seen in the Outpatient Department of the Antonio Lorena´s Hospital. 
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History: 62 yo male patient with a 5-month history of an extremely painful lesion on the palate, that caused difficulty in ability to eat and drink and 1 month of fever and increasing shortness of breath. He reports a weight loss of approx. 10kg and a cough productive of yellowish with occasional blood streaking.

Epidemiology: Born in Cusco, but has resided the past 45 years in Tambopata, Madre de Dios, in the jungle as a farmer. Wife died 10 years ago of pulmonary tuberculosis and his son was successfully treated for gastrointestinal tuberculosis at the same time. The patient did not receive isoniazid preventive treatment.

PMH: Treated 20 years earlier with an incomplete course of antimony for a chest ulcer which showed leishmania on a scraping. No recurrent skin ulcers.

Physical Examination: BP: 85/60 mmHg, HR: 98x’; RR: 37x’; T°:36°C, Sat02: 85% at FiO2 21%. On examination, the patient appears chronically ill with wasting and respiratory distress. Oral Exam: friable ulcer with well-defined edges on the hard palate. Chest: Respiratory sounds audible with crackles and rhonchi bilaterally. Skin: Pallor of skin and mucous membranes. Abdomen: no visceromegaly. Neurologic examination: normal.

Laboratory Examination and Imaging: Hematocrit: 41%. Hemoglobin:14.8 g/dl. WBC: 6.1 (0% bands, 65% segmented neutrophils, 3% eosinophils). Platelets: 397 000. Creatinine: 0.8mg/dl. Urea:36 mg/dl. Glucose: 87 mg/dl. Alkaline phosphatase: 119. AST/ALT: 27/37, Albumin: 4.5. Blood Culture x 2: Negative. Stool negative for ova and parasite including Strongyloides stercoralis. Chest X-ray: bilateral nodular and alveolar infiltrates (Image A). Chest CT-Scan: bilateral nodular lesions, some with cavitation, reticulo-nodular infiltrates and bilateral alveolar infiltrates (Image B).

UPCH Case Editors: Carlos Seas, Course  Director / Karen Luhmann, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Cryptococcus neoformans, disseminated form. HTLV-1 infection.
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Discussion: India Ink staining was positive from sputum and oral ulcer specimens, but negative from urine and CSF samples. Cryptococcus neoformans was isolated in culture from a tissue sample obtained from the oral ulcer; the India ink stain of the culture shows spherical structures with a thick capsule and single peripheral budding (Image C). AFB staining and TB cultures of sputum, stool and urine samples were negative. HIV 1-2 ELISA: Negative. RPR: negative. HTLV 1-2 ELISA: Positive. Cerebrospinal fluid: Opening pressure 16 cmH2O with 1 white cells, glucose 44 mg/dl (normal), normal protein, Gram stain negative, India ink negative and bacterial culture negative. Culture and smear for leishmania from the oral ulcer negative.

The differential diagnosis of the pulmonary presentation in this case includes paracoccidioidomycosis, histoplasmosis, tuberculosis, leishmaniasis, Kaposi´s sarcoma, and Wegener´s granulomatosis. Paracoccidioidomycosis (PCM) will be the main differential diagnosis in this case. In the chronic multifocal form of PCM oral ulcers are located mostly on the hard palate and have a characteristic fine granular pattern with multiple small hemorrhagic dots, ulcers are very painful and are almost always accompanied by pulmonary involvement, a nodular pattern as in this case, is less common.

Fungi of the Cryptococcus neoformans/Cryptococcus gattii complex are encapsulated, cosmopolitan yeasts 2–10 mm in diameter. C. neoformans var neoformans (serotypes A and D, genotypes VNI–IV) and C. neoformans var gattii (serotypes B and C, genotypes VGI–IV) make up the complex. About 95% of cases are caused by var neoformans, and serotype A (var grubii) is responsible for 95% of those which has a ubiquitous distribution worldwide.

Cryptococcosis can be seen in both apparently immunocompetent and obviously immunosuppressed hosts. Patients with weak cellular immunity are predisposed to present with disseminated disease, most commonly those with HIV. Pulmonary involvement in cryptococcosis is characterized by a wide range of manifestations depending on the degree of immunosuppression, from asymptomatic patients to rapidly progressive disease [Current Opinion Infect Dis 2009;15:254-260]. Pulmonary nodules, reticulonodular infiltrates, segmental or lobar consolidations, mediastinal and hilar adenopathies and less frequently pleural involvement are reported. Our patient presents with a mixed nodular, alveolar and interstitial pattern.

HTLV-1 is endemic in certain areas of the globe including Latin America (Lancet Infect Dis. 2007 Apr;7(4):266-81). A study conducted in Quillabamba, Cuzco, near the place this patient and his parent were born showed an overall prevalence of HTLV-1 infection of 5.1% among 370 individuals evaluated [Am J Trop Med Hyg 1997;56:561]. No information on the status of HTLV-1 infection on his parents was available. He likely got the infection by breastfeeding. A number of clinical conditions are associated with HTLV-1 infection; [see Lancet Infect Dis. 2007 Apr;7(4):266-81 for a detailed discussion]. Included are those caused by autoimmune mechanisms such as tropical spastic paraparesis (TSP), also called HAM (HTLV-1 associated myelopathy) [see Gorgas Case 2002 #8], uveitis, Sjögrens, arthropathy, thyroiditis and polymyositis; cellular immunosuppression such as strongyloides hyperinfection [see also Gorgas Case 2007 #4]; infective dermatitis [see Gorgas Case 2004 #7], crusted scabies (see also Gorgas Case 2013 # 10), tinea corporis, tuberculosis; and oncogenic mechanisms including ATLL (see Gorgas Case 2016 #05) . More recently, a probable association with endemic fungal infections including paracoccidioidomycosis and histoplasmosis has been proposed (Clin Infect Dis 2010;51:250-251 and J Infect Dev Ctries 2011;5:484-488). HTLV-1 infection may alter the immune response to endemic infections including endemic mycoses leading to severe clinical presentations, but this has not been studied yet. Few published reports of cryptococcal disease in patients with HTLV-1 are available. Skin and pulmonary involvement in an HIV-negative patient from Dominica was reported, no mucosal involvement was mentioned [JEADY 2003;17:723-724]. Localized lymphadenitis was reported from Japan in one patient [J Clinical Experimental Histopathol 2017;57:26-30].

The current Infectious Disease Society of America treatment guidelines for patients with pulmonary cryptococcosis recommend to first rule-out meningeal involvement [Clin Infect Dis 2010; 50:291-322]. Non-HIV-infected, non-transplant patients with evidence of disseminated disease outside of the lungs, as in this case, should be treated as per patients with CNS disease with amphotericin B deoxycholate plus flucytosine for 4-week induction therapy, followed by fluconazole for 6-12 months. In settings where flucytosine is not available, extending duration of amphotericin B is recommended. There are no specific recommendations for treating HTLV-1 infected patients. This patient was treated only with a 2-week course of intravenous amphotericin-B deoxycholate plus fluconazole as he requested discharge against medical advice, and was switched to oral fluconazole to complete a one-year course of treatment. The clinical evolution of our patient has been favorable, with disappearance of fever and improvement of respiratory distress. He is being follow by our colleagues in Cuzco.

We would like to thank Dr. Fatima Concha for presenting the case to the class and to Dr. Peter Pappas for contributing to the discussion.
University of Alabama at Birmingham

Gorgas Case 2018-04

Universidad Peruana Cayetano Heredia
The following case was seen on the inpatient ward of Cayetano Heredia Hospital in Lima by the 2018 Gorgas Course participants. 
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History: At 8pm, a 68-year-old male was bitten twice, on the index and middle fingers of his right hand, while trying to catch a snake outside his house. At first, there was only mild stabbing pain, but after 1h the hand had become swollen and tender. These symptoms increased, prompting his presentation to the ED 3½h after the bites.

Epidemiology: He was born in Huancayo but had dwelled in Lima since he was 14 years old apart from trips to Tarapoto and Tingo Maria in the Amazon region. He lives in Collique, a hilly (cerro) northern suburb of Lima, 20 k north of UPCH. His house is made of mats and has no cement floor. He works selling Aloe plants in a market.

Physical Examination: BP: 110/70mmHg. HR: 61. RR: 20. T: 36C. Sat 98% at FiO2 21%. The patient felt hot and sweaty. There was tense, tender swelling and erythema of the fingers and right hand extending up to the elbow. He had tender enlarged lymph glands in the right axilla. By the next day, the whole right arm was swollen and he was unable to raise his right arm because of stiffness and pain (Image A). Subsequently, more bruising appeared on the right arm and the right side of his chest (Image B) and his hand and arm felt numb.

Laboratory: Hematocrit:36%. Hemoglobin:12 g/dl. WBC: 10.6 (0% bands, 63.5% segmented, 10.2% eosinophils) Creatinine:0.9mg/dl. Urea:31 mg/dl. INR: 1.19, PT: 14.9, aPTT: 38.5. Whole blood clotting time: 6min. Bleeding time: 3min. Urine Exam: density 1024, pH 5, 2-3leu/field, 2-3 RBC/field, sparse epithelial cells.

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

Envenoming by desert lancehead pit viper (Bothrops pictus or B. roedingeri)

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Species diagnosis
After being bitten, the patient killed the snake, cut off its head and bit its tail for superstitious reasons. These sorts of rituals are common in regions where snake-bites are common, reflecting people’s almost supernatural dread of venomous snakes. The reason he gave us for trying to catch a dangerous snake was that he wanted to use the skin, as “leather”, to make some kind of art work. He had killed a similar snake only one week previously. His family was asked to bring in the remains of the snake to allow a species diagnosis, but, initially, only the headless skinned body was provided, which was impossible to identify! Finally, they were persuaded to bring the flayed skin, whose dark blotched and zig-zagged dorsal pattern and rough scales were diagnostic of the desert lance-headed pit vipers (Bothrops pictus and B. roedingeri) (“jergón de la costa”, or “víbora”) (Image C), the only venomous species found in the Lima area. [Campbell, JA, Lamar, WW. (eds.) The Venomomous Reptiles of the Western Hemisphere. Ithaca, Comstock Cornell University, 2nd Ed 2004]. The snake must have exceeded 49 cm in total length, the combined lengths of the body fragments without head and tail tip. Bothrops pictus and B. roedingeri are endemic Peruvian species (Image D & E) found on the western slopes of the Andes, and throughout the coastal foothills and mountains at altitudes between sea level and 2,300 m, from Ancash south to Arequipa. They also occur in some of the drier inland valleys and mountains, such as Chillon and Canta, and cerros in the Cono Norte of metropolitan Lima. These two species are superficially similar in appearance, have been widely confused and, indeed are, according to some authorities, the same species (http://reptile-database.reptarium.cz/species?genus=Bothrops&species=pictus). Bothrops roedingeri differs from B. pictus in being longer and more slender (up to 100cm in total length compared to 60cm), having fewer dorsal scale rows and more ventral scales, and inhabiting lower altitudes closer to the coast as far North as La Libertad [Campbell, JA, Lamar, WW. (eds.) The Venomomous Reptiles of the Western Hemisphere. Ithaca, Comstock Cornell University, 2nd Ed 2004]. 

Evolution of envenoming
After receiving two bites on fingers of his right hand, our patient developed, over the next few days, progressive pain, dysfunction, swelling and bruising of the entire arm, axilla and right side of his trunk (Image B) which had largely resolved by the time he was discharged 12 days later. He had no symptoms of systemic envenoming. It is interesting that his extensive local bruising occurred, despite the lack of coagulopathy or thrombocytopenia, implying direct damage to the endothelium of adjacent blood vessels by large molecular weight snake venom haemorrhagins that had spread through the lymphatic system from the site of the bite [Toxins (Basel). 2016;8(4):93]. Literature reports and local snake-bite experts in the Lima area have not distinguished bites by B. pictus from those by B. roedingeri. A study of 23 patients with presumed B. pictus bites admitted to Cayetano Hospital in 1990-1998 described local swelling, erythema, bruising (sometimes extensive), and blistering as the commonest features [Folia Dermatol Perú 1998;.9: 41-48]. Coagulopathy was detected in 6 of 8 cases and one developed acute kidney injury. 75% were treated with INS antivenom and there were no fatalities. However, our patient had heard of a recent snake-bite fatality in Puente Piedro, also in the Cono Norte of Lima.

Envenoming is not inevitable after a bite by a venomous snake even when fang puncture marks are evident on the skin. The phenomenon of “dry bite” has been well documented in about 50-80% of snake-bite victims [Toxicon 2017;133:63-67]. It was well illustrated by a patient seen in the ED of Cayetano Hospital only 12 days after our patient was admitted. Despite fang marks and the evidence of a dead desert lancehead, he developed no symptoms or signs of envenoming.

Mechanism of haemorrhage
The venom of B. pictus contains an array of toxic proteins and peptides typical of Viperidae, but compared to some other Peruvian pit vipers, such as the notorious B. atrox of the Amazon region (see case 2, 2014), it has a higher proportion of haemorrhagins [J Proteomics 2012;75(7):2181-95]. These are large molecular weight P-III snake venom metalloproteinases (SVMPs) that possess an N-terminal Zn2+ - dependent catalytic domain, disintegrin-like domain and C-terminal cysteine-rich region. They degrade matrix proteins in the capillary basement membrane, resulting in spontaneous systemic haemorrhage, a dangerous effect of envenoming [Toxins (Basel) 2016;8(4):93]. A variety of venom toxins, including SVMPs, and an L-amino acid oxidase from B. pictus venom, can inhibit platelet agglutination [Toxicon 2017;139:74-86]. Although our patient did not develop thrombocytopenia, his platelet function may have been impaired, contributing to the extent of local bleeding.

Access to antivenom treatment
Our patient was initially frustrated in his search for appropriate treatment. First, he went to the local hospital, but, after 2h, was sent away because no antivenom could be found. He then visited another hospital 11k away, but it also lacked this essential drug. Finally, at UPCH, he was given antivenom because of the extent and progression of the local swelling, even though there was no evidence of systemic envenoming. One vial of Peruvian Instituto Nacional de Salud (INS) suero antibotrópico polivalente was administered 13 h after the bite, and a second vial 3 h later, without any adverse reactions. He felt relief of pain 3h after the second dose. This antivenom is raised in horses by hyperimmunising them with venoms of desert lancehead (Bothrops pictus), common lancehead (B. atrox), Brazil’s lancehead (B. brazili), Barnett’s lancehead (B. barnetti) and hognosed lancehead (Bothrocophias hyoprora) and extracting whole IgG from the resulting plasma by ammonium sulfate fractionation [Toxicon 2016;122:67-77]. Preserved specimens of four of these species, loaned by INS, were studied by the Gorgas participants during a pioneering snake identification workshop (Image F).

We would like to thank Professor David Warrell, Emeritus Professor, Oxford University,  for providing insightful case discussion.

University of Alabama at Birmingham

Gorgas Case 2018-03

Universidad Peruana Cayetano Heredia
The following case was seen on the inpatient ward of Cayetano Heredia Hospital in Lima by the 2018 Gorgas Course participants.
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History: 68-year-old man admitted with varicose ulcers of both legs with superinfection characterized by increasing purulent secretion and fever. Hospitalized twice previously over the last 4 years for the same problem. During the current hospitalization, patient noticed the development of painful erythematous subcutaneous nodules on the upper limbs, thorax, abdomen and thighs. He reports episodes of similar painful nodular lesions for the last 6 years.

Epidemiology: Born in Piura on the north coast of Peru, moved to Lima and has been living there for the past 50 years. No known TB contacts.

Physical Examination: BP: 110/70 mmHg. HR: 70 bpm. RR: 20 rpm. T: 37. Sat: 98 % (FiO2: 0.21). No apparent distress with clear mentation. Skin: Multiple dermal and subcutaneous nodular erythematous lesions, mobile, tender, 2 x 1.5 cm localized over the upper limbs, anterior and posterior thorax and abdomen, some of these have pustules on the top (Image A and B). Conglomeration of very painful and extremely tender nodules on both thighs. Nodules had a yellowish content. No lesions on the face. Chest: clear to auscultation bilaterally, no crackles. Cardiovascular: regular heartbeat, no murmurs. Abdomen: soft, non-distended, normal bowel sounds, not tender to palpation. Neurological: Decreased muscle strength in the right cubital territory and thickened superficial branch of the left radial nerve plus hypoesthesia in both hands and anesthesia on both feet. Cranial nerves: afferent corneal sensation decreased bilaterally.

Laboratory Examination (on admission): WBC 20.2 (0% bands, 82.7% segmented, 1.6 % eosinophils, 4.8% monos, 10% lymphs). Hb 9.8g/dl. Hct 31%. Platelets 319 000. Glucose 109mg/dl. Urea 47.2. Creatinine 0.8mg/dl. Blood Culture x 2: negative.

UPCH Case Editors: Carlos Seas, Course  Director / Karen Luhmann, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Mycobacterium leprae. Erythema nodosum leprosum. Treated lepromatous leprosy (LL).
Images for Case 2018-03
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Discussion: Smear of a pustule was taken from one nodule on the right upper arm and a Fite-Faraco stain showed a hypocellular smear composed mainly of neutrophils (red arrow) and numerous clustered bacilli (black arrow) (Image C). Additionally, a skin biopsy of a nodule from the anterior chest wall was performed, Fite-Faraco staining of a skin biopsy over a chest-wall nodule showed foam cells (black arrow) and many acid-fast bacilli (yellow arrow) (Image D).

When first seen by us 2 years earlier he presented with areas of infiltrated skin all over the body, multiple papular lesions as well as tender dermal and subcutaneous nodules on the upper limbs, thorax, abdomen and thighs characteristic of lepromatous leprosy. He was treated with a complete course of WHO multi-drug therapy (MDT) for 1year. Patients with lepromatous leprosy have no cell-mediated immunity against the bacterium, so the bacteria are always killed by 1-year of therapy but they remain in the body because these patients cannot eliminate them, they will disappear progressively over several years.

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. Type 2 inflammatory reactions, such as seen here have as the most common presentation erythema nodosum leprosum (ENL). 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. This is a systemic immune mediated disorder, associated with antigen-antibody immune-complex deposition in tissues, usually with high levels of tissue and circulating TNF-alpha.

Lepromatous patients have high levels of antibodies and high levels of antigens (bacterial load) and they produce immune complexes. ENL presents usually with many tender dermal and subcutaneous erythematous nodules that occurs in up to 50% of lepromatous leprosy cases [Am J Trop Med Hyg. 2006;74:868-79] and 25% of borderline lepromatous patients [Dermatology Online J 2006; 12:29], due to their high bacterial loads. The lesions of ENL differ from the common erythema nodosum in that the nodules occur anywhere in the body rather than on the shins, whereas in erythema nodosum they occur on the shins and rarely in other places. On the shins erythema nodosum lesions are difficult to hold, they are more plaque-like, whereas ENL lesions in other areas are easily hold as a subcutaneous nodular lesion. In addition, ENL nodules may ulcerate and drain pus, with no pyogenic bacteria but with usually dead leprosy bacilli. The PAP smear of the content of the nodules in this patient showed a hypocellular smear composed mainly of neutrophils with abundant bacilli on Fite Faraco staining (Image C). As long as patients have bacteria (antigens) they produce immune complexes and may precipitate ENL repeatedly several years after therapy. Clinically, a relapse would not be suspected in this patient, due to lack of new infiltrative areas on the skin and no new peripheral nerve involvement, so he only needs therapy for the reaction. ENL histopathology shows an infiltration by neutrophils, which is not seen in a biopsy of leprosy without type 2 reaction.

ENL may also produce to varying degrees, fever, neuritis, edema, arthralgias, leukocytosis, uveitis, dactylitis, periostitis, orchitis, lymphadenitis and nephritis. ENL may occur in patients prior to therapy (onset 4 years before therapy in this case), during therapy and/or after therapy until the antigen load decreases markedly. ENL may present as repeated acute episodes, such as in this patient, or may be chronic or ongoing.

ENL can be treated symptomatically if mild or with prednisone or thalidomide if severe. Thalidomide is the drug of choice for severe ENL as in this case and very effective for neuritis due to type 2 reaction. A dose of 300 to 400 mg daily will usually control the reaction within 48 hours. The dose is then tapered usually every 7-10 days to a maintenance level, which is generally around 100 mg daily and then attempts are made to taper off the drug. This patient has been having recurrent severe ENL beginning 4 years prior to his MDT treatment. Uncontrolled ENL can lead to secondary amyloidosis.

In cases of difficult to treat ENL, some drugs reported as useful have been azathioprine [J Clin Diag Res 2017;11:FD01] minocycline [JAMA Dermatol 2015;151:1026], and etanercept [Ann Bras Dermatol 2017;92:575 and Clin Infect Dis 2011;52:e133].

We would like to thank Pedro Legua MD, Universidad Cayetano Heredia, for providing insightful case discussion.

University of Alabama at Birmingham

Gorgas Case 2018-02

Universidad Peruana Cayetano Heredia
The following case was seen in the ICU of Cayetano Heredia Hospital in Lima by the 2018 Gorgas Course participants.
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History: 79-year-old man is brought to the ER after having vomited twice over the previous 4 hours approximately 200 cc of blood clots, and experienced one episode of black stools. Denies abdominal pain or nausea. After a new episode of hematemesis in the ER (Image 1) the patient was admitted to the ICU for vasopressor support.

Past Medical History: Intermittent cough and wheezing over the course of the last year, with intermittent, salbutamol, dexamethasone or prednisone (most recently a single dose of 20 mg prednisone 1-2 months prior to presentation).

Epidemiology: Born in Piura on the north coast of Peru, moved to Lima and has been living there for the past 50 years. No known TB contacts.

Physical Examination: Patient is admitted in a wheelchair, awake, breathing spontaneously, appears acutely ill. BP: 52/36, HR: 89, RR: 18, Sat: 96 % (FiO2: 0.21). Skin: pale. Chest: clear to auscultation bilaterally, no crackles. Cardiovascular: irregular heartbeats, no murmurs, no S3. Abdomen: soft, mild distended, bowel sounds heard, not tender to palpation. Gross melena on rectal exam.

Laboratory Examination (on admission): INR: 6.47, PT: 13, aPTT: 66.5. WBC 12.6 (0% bands, 84% segmented, 1% eosinophils). Hb 7 g/dL, Hct 22%. Platelets 176 000. Glucose 197 mg/dl. Urea 161.7 mg/dl. Creatinine 1.3 mg/dl.

UPCH Case Editors: Carlos Seas, Course  Director / Karen Luhmann, Associate Coordinator
UAB Case Editor: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director
Diagnosis: Massive infestation with Ascaris lumbricoides
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Discussion: Upper endoscopy was technically difficult due to persistent bleeding. Endoscopy Report: A large blood clot is observed, which does not allow visualization of the gastric fundus. No active bleeding observed in the pylorus, duodenal bulb, or second portion of the duodenum. Helminth debris are found throughout. The incidental presence of massive Ascaris lumbricoides infestation in this patient with unrelated gastrointestinal bleeding and elevated INR was made by examination of the content of the vomitus from the initial presentation (Image 2-3). A stool O & P was negative for both Strongyloides stercoralis and hookworm both of which may cause bleeding in some circumstances.

Ascaris lumbricoides infects an estimated 800M people mostly in the tropics with year-round transmission. Latin America accounts for approximately 8% of the total burden of infection. Children are most affected (particularly under 10 yo) but adults can also be infected. A study conducted in the Andean area of Ayacucho, Peru found that the prevalence of Ascaris lumbricoides was 4.5% among patients of all ages (Rev Gastroenterol Peru 2005;25:150). Higher rates of infection (37% among school-aged children) have been reported in a similar community in Peru (Osong Public Health Res Perspect 2017;8:302).

Humans get the infection by ingesting either food or water contaminated with eggs that hatch in the small intestine releasing larvae that migrates to the large intestine and cross the intestinal wall to migrate to the lungs via lymphatic or hematogenous spread. Within the alveoli, larvae mature over 14 days to migrate to the bronchial tree to be then swallowed finally to be located in the small intestine, mostly in the jejunum. Adults do not multiply in humans; worm burden can be extremely large.

Most infections are asymptomatic. During the lung passage of larvae (5-15 days after ingestion) patients may present with dry cough, fever, dyspnea and blood-tinged sputum. Wheezing can be detected on physical examination. Peripheral eosinophilia can be observed as well as migratory pulmonary infiltrates, especially when the burden of parasites is large. Our patient complained of respiratory symptoms for one year before admission, likely as a result of pulmonary migration of larvae. Eggs are not detected in the stools of these patients as the larvae must mature in the intestine later on.

Intestinal manifestations are non-specific and include abdominal pain, nausea and diarrhea. When the intestinal burden is large, complications such as intestinal obstruction can be seen (Rev Chilena Infectol 2016;33:572), the ileocecal valve is the usual place of obstruction. on rare occasions, adults migrate to the biliary tract causing cholangitis, pancreatitis, and hepatic abscesses (see case 2002-05). As adult ascaris lie free in the intestinal lumen, gastrointestinal bleeding is not a complication of ascariasis.

Diagnosis is generally made by detecting eggs for which the Kato-Katz test is recommended, its sensitivity has been more recently questioned compared to the Lumbreras rapid sedimentation method for detecting A. lumbricoides (85% vs. 95%, Pathog Glob Health 2016;110:130). Adult worms are sometimes regurgitated through the mouth or nose especially in children and because of the large size can be diagnosed on gross morphology as is the case in our patients. Adult worms may also be passed per rectum.

Ascaris is exquisitely sensitive to all the usual antihelminthic agents used for intestinal helminths including albendazole, mebendazole, pyrantel pamoate, and piperazine (still used in resource-limited settings).

University of Alabama at Birmingham

Gorgas Case 2018-01

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 18th 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 case was seen on the Inpatient Ward of Cayetano Heredia Hospital in Lima by the 2018 Gorgas Course participants.
Image for Case 2018-01
History: 26-year-old MSM patient came to the emergency department complaining of two-month history of productive cough, fever, night sweats, dyspnea, weight loss of 10Kg in the last month, asthenia, diarrhea, and mild lower gastrointestinal bleeding (blood spots on his underwear). One week prior to admission the patient noticed a painless ulcerative lesion on the sacral region.

Past Medical History: Diagnosed in 2015 with HIV, (CD4=293 cells/mm3; viral load= 462,981 copies/ml. HAART (with zidovudine, lamivudine and efavirenz) was taken irregularly and stopped the medications two months ago with (CD4=18 cells/mm3; viral load=905,000 copies/ml.

Epidemiology: Born in Pucallpa (jungle), moved to Ancash (highlands), at the age of 6 and has been living in Lima for the past 10 years. No known TB contact. Denies alcohol or drug consumption.

Physical Examination: Pulse: 110; respirations: 28 SatO2:96% on 2l/min O2; BP: 102/61 mmHg; T:39,5C Patient in obvious respiratory distress. Skin: Pallor ++/+++, non-painful sacral ulcer 3x5cm with regular borders. (Image 1). Bilateral cervical lymphadenopathy. Chest: no rales in both lungs. Abdomen: normal bowel sounds, soft, non-tender, non-distended. No hepatosplenomegaly.

Laboratory: Hemoglobin: 7.9 g/dl;, Hematocrit: 24%, WBC: 1,200; neutrophils:78%. Platelets: 95,000. Glucose: 106 mg/dl, Creatinine: 0.6 mg/dl. Alkaline Phosphatase: 1023 IU/l (N<126); LDH: 395 U/L (N=313-619); beta2 microglobulin: 3113 ng/ml (900-2700) Sputum AFB: negative x 3, culture pending. CT scan of the chest is shown (Image 2).

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

Diagnosis: Progressive disseminated histoplasmosis (PDH) due to Histoplasma capsulatum
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Discussion: Histoplasma capsulatum was isolated from bone marrow culture. Image 3 shows diagnostic macroconidia with tuberculated typical thick walls that are large and round about 8-16 microns. Definitive diagnosis in these cases is made by fungal isolation (from bone marrow, blood or tissue samples including lymph nodes, skin or oral lesions) as a gold standard. 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. 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. In normal hosts, a self-limited pulmonary infection with mediastinal adenopathy is most common, but opportunistic disseminated infections in patients with depressed immunity, especially those with AIDS, is frequent. Endemic areas are the Mississippi, Ohio and St. Lawrence valleys in the USA, the Caribbean, Mexico and Latin America, South East Asia and Africa. 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. The Chest CT scan (Image 2) showed an interstitial infiltrate mainly composed of micronodules compatible with a milliary pattern. The differential diagnosis of these CT findings in a patient with HIV includes TB, PCP, penicilliosis (found mainly in Southeast Asia) and lymphoma. The differential diagnosis of the skin lesions in this patient includes herpes simplex infection, tuberculosis, paracoccidioidomycosis and cancer.

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); interestingly, 35% had TB as well. Predictors of PDH were significant weight loss, hepato or splenomegaly, skin lesions and hematologic abnormalities (mainly pancytopenia), all 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). Co-infections are common. Among 45 patients in Colombia, 23 had other infections, 70% had TB and 13% had PCP or cryptococcosis (Med Mycol Case Rep 2018;19:45)

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 was started empirically on anti TB treatment with standard 4-drug therapy and is currently receiving amphotericin deoxycholate. He will be started on ART within 2 weeks of induction therapy with amphotericin B.