Gorgas Case of the Week - 2020 Series

University of Alabama at Birmingham

Gorgas Case 2020-07

Universidad Peruana Cayetano Heredia
The following patient was seen as an outpatient at Hospital Cayetano Heredia during the Gorgas Diploma Course. We would like to thank Dr. Rodrigo Cachay for his assistance with this case.
Image for Case 2020-07

History: A 27-year-old woman presented at 10 weeks of pregnancy with a pruriginous generalized rash associated with malaise and subjective fever, which resolved within a week without any treatment. Routine obstetric ultrasounds were reported as normal up to the 25th gestational week when estimated fetal weight was shown to be below the 1st percentile, and a diagnosis of severe intrauterine growth restriction was made. Additionally, fetal periventricular, basal ganglia and intraparenchymal calcifications were described, along with right ventriculomegaly, lissencephaly, and calcification of mitral valves. A male baby was born at 36 5/7 weeks.

Epidemiology: Mother denied any past medical history or drug use. Born and lived in Jaen, Cajamarca, in the high jungle of Peru. Received all recommended immunizations for pregnant women as per national guidelines.

Physical Examination: At birth: Weight 1900g, height 45cm, head circumference 28cm (less 3rd percentile). The patient had evident microcephaly, retrognathia, and valgus deviation of lower extremities with a left club foot (Images A and B). At two months of age: The patient appeared malnourished. No skin findings. The pulmonary exam was normal and the cardiovascular exam revealed an I/VI systolic murmur in precordium. On neurological examination, the patient was excitable, had a punctiform fontanelle, hypertonic posture with distal quadriparesis, and did not follow objects with the eyes. Reflexes were normal and cranial nerve examination was unremarkable. Fundoscopy was normal.

Imaging Studies: Hip ultrasound: type II de Graff hip. X rays of extremities: signs of mild hip dysplasia, deformation of the longitudinal axis in knees. Echocardiography: Mild left hypertrophic cardiomyopathy with preserved systolic function and diastolic dysfunction, indirect signs of mild pulmonary hypertension.

Laboratory: Normal CBC. IgM for rubella, cytomegalovirus, herpes I and 2, toxoplasma were negative. Mother was also negative for TORCH and HIV.

Further examinations: Electroencephalogram showed low asymmetric activity predominantly at the left hemisphere, no paroxysms. Evoked auditory and visual potentials were normal.

UPCH Case Editors: Carlos Seas, Course  Director / Alvaro Schwalb and Paloma Carcamo, Associate Coordinators

UAB Case Editors: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director


Diagnosis: Congenital Zika virus infection

Images for Case 2020-07
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Discussion: RT-PCR for Zika virus for the mother came back positive and close monitoring of her pregnancy ensued. Zika PCR and serology for the newborn was unavailable. A brain CT revealed microcephaly, bilateral calcifications of basal ganglia and frontal white matter, pachy-polymicrogyria in both hemispheres, and ventriculomegaly (Image C). Brain MRI showed bilateral frontal pachygyria, temporal, parietal and occipital bilateral lissencephaly, and dysplasia of the corpus callosum (Image D).

Zika virus is flavivirus transmitted by mosquitoes, most commonly Aedes aegypti. It is closely related to other flaviviruses such as dengue, yellow fever and West Nile virus. Although it was first isolated in 1947, the first major outbreak occurred in 2007 in Micronesia, with an estimated 5000 infections among a population of 6700. By 2014, the virus had made its way to Latin America and after five years the largest number of cases were reported in Brazil (231,725), Colombia (98,803) and Venezuela (60,146) (PAHO/WHO). The first cases of Zika virus in Peru were reported in 2016 in the regions of Cajamarca and Loreto; last year, during the patient’s mother’s pregnancy, there was an active outbreak in the city of Jaen from February to August with a cumulative incidence of 1869 cases.

Congenital transmission of Zika virus can occur at any moment during pregnancy and even peripartum, but the highest risk for fetal sequelae occurs with first and second-trimester infections. Following maternal infection, the virus is believed to infect the placenta and migrate to the fetal brain, where it causes apoptosis of neural progenitor cells (Curr Opin Virol, doi:10.1016/j.coviro.2017.09.005).

Acute Zika virus infection presents with non-specific symptoms including maculopapular pruritic rash, fever, arthralgia, conjunctivitis, myalgia, and headache. It has been strongly associated with Guillain-Barré syndrome (N Engl J Med, doi: 10.1056/NEJMra1602113). Congenital infection causes a wide range of clinical manifestations in the fetus. Fetal cranial morphology may be severely altered, with microcephaly, overlapping cranial sutures, and redundant scalp skin, with extreme craniofacial disproportion. Brain anomalies such as subcortical intracranial calcifications, increased fluid spaces, cortical thinning and abnormal gyral patterns, hypoplasia or absence of the corpus callosum, decreased myelination and cerebellar hypoplasia are frequently associated. Ocular abnormalities such as cataracts, intraocular calcifications, chorioretinal atrophy, and optic nerve anomalies have also been reported. Congenital musculoskeletal abnormalities such as arthrogryposis and clubfoot are commonly observed as well, probably due to affection of the corticospinal tract or motor neurons. Cardiac abnormalities have a reported prevalence of around 10%, and are usually not severe (PLOS Negl Trop Dis, doi: 10.1371/journal.pntd.0006362). Five to ten percent of pregnancies with documented Zika infection result in fetal loss (JAMA Pediatr, doi: 10.1001/jamapediatrics.2016.3982). In the case presented, the patient had evidence of significant musculoskeletal and neurological involvement, as evidenced in the physical exam and brain imaging.

Diagnosis is made by detection of viral nucleic acid by PCR or of IgM antibodies by ELISA. Viremia is usually transient, though it may last longer in pregnant women with evidence of fetal congenital infection, so a negative PCR does not rule out the diagnosis. IgM is thought to appear as viremia fades, within the first week after symptom onset, and it typically persists for months. Serology may cross-react with other flavivirus such as dengue (N Engl J Med, doi: 10.1056/NEJMra1602113). There are no reliable tests for prenatal and antenatal diagnosis of congenital Zika virus infection, although in some cases the amniotic fluid or cord blood might have a positive PCR. The diagnosis is confirmed by positive serum, urine of cerebrospinal fluid PCR for Zika virus in the newborn, in samples collected within the first two days of life (MMWR Morb Mortal Wkly Rep, doi: 10.15585/mmwr.mm6641a1).

The differential diagnosis for congenital Zika infection must include other congenital infections that may cause microcephaly such as rubella, cytomegalovirus or toxoplasmosis. Rubella typically presents with congenital glaucoma and pigmentary retinopathy. Cytomegalovirus presents with a periventricular pattern of intracranial calcifications, as opposed to the subcortical distribution in Zika infection. Toxoplasmosis usually presents with diffuse intracranial calcifications. Of note, congenital Zika infection does not present with hepatosplenomegaly nor skin lesions (Am J Public Health, doi: 10.2105/AJPH.2016.303115) Although these findings may help differentiate between different entities, the final diagnosis must be made with virologic studies. Non-infectious causes of congenital abnormalities must also be ruled out.

Patients with suspicion of congenital Zika virus infection should have a head ultrasound and a comprehensive ophthalmologic exam during their first month of life, as per CDC recommendations. There is no specific treatment, but patients should receive supportive management for complications (MMWR Morb Mortal Wkly Rep, doi: 10.15585/mmwr.mm6641a1).

Prevention centers on avoiding mosquito bites through usage of mosquito repellent, bed nets, and window screens, and applying permethrin on clothes. Pregnant women should not travel to endemic areas. There is no vaccine against Zika, although there are several candidates in clinical phase I/II trials (Cell Host Microbe, doi: 10.1016/j.chom.2018.05.021).

Our patient is being followed up by a multidisciplinary team comprised of pediatric neurologists, cardiologists, orthopedic surgeons, dietitians and, and undergoing physical therapy for hypertonicity.

● PAHO/WHO https://www.paho.org/hq/index.php%3Foption%3Dcom_content%26view%3Darticle%26id%3D12390:zika-cumulative-cases%26Itemid%3D42090%26lang%3Den
● Curr Opin Virol, doi:10.1016/j.coviro.2017.09.005 https://www.ncbi.nlm.nih.gov/pubmed/29080429
● N Engl J Med, doi: 10.1056/NEJMra1602113 https://www.ncbi.nlm.nih.gov/pubmed/27028561
● PLOS Negl Trop Dis, doi: 10.1371/journal.pntd.0006362 https://www.ncbi.nlm.nih.gov/pubmed?term=29579059
● JAMA Pediatr, doi: 10.1001/jamapediatrics.2016.3982 https://www.ncbi.nlm.nih.gov/pubmed/27812690
● MMWR Morb Mortal Wkly Rep, doi: 10.15585/mmwr.mm6641a1 https://www.ncbi.nlm.nih.gov/pubmed?term=29049277
● Am J Public Health, doi: 10.2105/AJPH.2016.303115 https://www.ncbi.nlm.nih.gov/pubmed?term=26959258
● Cell Host Microbe, doi: 10.1016/j.chom.2018.05.021 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6112613/

University of Alabama at Birmingham

Gorgas Case 2020-06

Universidad Peruana Cayetano Heredia
The following patient was seen as an inpatient at Hospital Antonio Lorena in Cusco during the Gorgas Diploma Course. We would like to thank Dr. Fatima Concha for her assistance with this case.
Image for Case 2020-06

History: A 30-year-old female patient presents with a 6-month history of illness that presents with cervical, axillary and inguinal lymphadenopathies, malaise and weight loss. One month before admission, she notices something moving in her scalp. Two weeks prior to admission, she starts noting abdominal distention.

Epidemiology: Born and lives in Manuquiari, La Convencion (Cusco), in the low jungle. Works as a homemaker and farmer. Part of the Matsiguenka native tribe. She is married. Denies previous illness. Denies any sick contacts.

Physical Examination: BP:90/60, HR 86, RR 18, afebrile. Skin and mucosae were pale. Elevated desquamative plaque in parieto-occipital area of the scalp (Image A). Painless ulcerated lesion with well defined, elevated edges and a clean base, on left knee (Image B). Painful ulcerated preauricular, postauricular and cervical lymphadenopathies, approx. 2cm in diameter, with purulent discharge (Image C). Lung examination revealed bilateral diffuse crackles. Heart auscultation was significant for a mitral systolic II/VI murmur. The abdomen was very distended, bowel sounds were present, it was dull on percussion, with a positive wave sign, with no collateral circulation. The liver was firm and markedly enlarged, with no splenomegaly. Neurological exam was normal.

Imaging StudiesChest x-ray showed a mild bilateral interstitial pattern (Image D). CT of the thorax revealed a bilateral fine ground-glass pattern, predominantly in bases, and mediastinal adenopathies (Image E). Abdominal ultrasound revealed an enlarged liver and abundant free fluid. Abdominal CT showed hepatomegaly, ascites and periaortic adenopathies (Image F).

Laboratory: Hb: 6 g/dL; Hct. 22%; WBC 11 540 (neutrophils: 90%, eosinophils: 2.95%, lymphocytes: 4.07%); Platelets: 374 000. INR 1.4, PT 19.7, PTT 40.5. Gluc: 90 mg/dL, Urea: 39 mg/dL, Creat: 0.38 mg/dL, AST 15, ALT 10, GGT 15, Alk Phos 98, total bilirubin 0.23 (direct 0.07), LDH 196, albumin 2.1. AFB in sputum, urine, feces, lymphadenopathy secretion: negative. HIV and HBsAg were non-reactive. VDRL negative.

Notes: Five different pathogens were isolated from this patient.

UPCH Case Editors: Carlos Seas, Course  Director / Alvaro Schwalb and Paloma Carcamo, Associate Coordinators

UAB Case Editors: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director


Diagnosis: Disseminated paracoccidioidomycosis, kerion (tinea capitis), myiasis, cutaneous leishmaniasis, intestinal hookworm infection.

Images for Case 2020-06
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Discussion: Direct microscopy with 10% KOH of secretion from the lymphadenopathies showed large oval yeast cells surrounded by budding daughter yeast cells, characteristic for Paracoccidioides spp (Image G). Direct microscopy of skin scrapings from the scalp lesion revealed multiple arthroconidia, making the diagnosis of tinea capitis. The patient had had fly larvae removed from this same lesion in the scalp prior to presentation in the hospital. Direct microscopy of skin scraping from the knee revealed abundant Leishmania sp. amastigotes (Image H). Direct microscopy of the stool revealed oval thin-shelled ova with blastomeres inside, corresponding to hookworm eggs (Image I). Baermann test for S. stercoralis was negative.

Paracoccidioidomycosis, also known as South American Blastomycosis, is a systemic fungal disease caused by Paracoccidioides brasiliensis and Paracoccidioides lutzii. It is endemic in the Americas, between the latitudes of 23°N and 23°S. Most reported cases occur in Brazil, with some reports from Colombia, Venezuela, Argentina, and Ecuador (https://www.ncbi.nlm.nih.gov/pubmed/29371520). There is scarce information about this disease in Peru, but all reported cases have a history of exposure to the high or low jungle (http://www.scielo.org.pe/scielo.php?pid=S1726-46342002000100009&script=sci_arttext).

Paracoccidioides spp. is a thermally dimorphic fungus, found in its mycelial form in soil and decaying vegetation. At body temperature, the fungus turns into yeasts, which can be seen as 4-40 μm oval budding cells. The two typically described structures on microscopic observation are the “boat steering wheel” conformation of a mother cell surrounded by blastoconidia, and the “Mickey Mouse ears”, a mother cell with two budding cells. This is in contrast to the round to oval multinucleate yeast cell with a single broad-based bud that is characteristic of Blastomycosis (https://cmr.asm.org/content/23/2/367). Reservoirs for this pathogen include humans and armadillos. Yeast forms may be found in biopsy samples of any affected organs, scrapings of superficial lesions, sputum samples, or in abscess or lymph node aspirates. Direct microscopy with KOH is positive in about 90% of cases, but samples can also be cultured in Sabouraud’s agar to increase diagnostic yield. Cultures usually take 20 to 30 days to grow, and may not be useful in informing timely clinical decision-making, and treatment should be started with direct microscopy findings. Serologies are useful as screening tests, but may cross-react with other dimorphic fungi, such as Histoplasma capsulatum (https://www.ncbi.nlm.nih.gov/pubmed/18380607).

Infection typically starts with inhalation of conidia. In a few patients, disease may occur a short time after infection (acute paracoccidioidomycosis). However, in most cases, the fungus remains in quiescent foci that can reactivate many years after primary infection, causing the chronic form of the disease. In endemic areas, it is estimated that up to 75% of the adult population may be infected, but only a few will show symptoms of the disease.

Disseminated paracoccidioidomycosis refers to disease involving multiple organ systems, as in the case of our patient. It is typically described in immunosuppressed hosts, usually HIV patients, solid organ transplant recipients, or patients with malignancies (https://www.ncbi.nlm.nih.gov/pubmed/15057336). Paracoccidioides coinfection with HTLV-1 has not been well studied, but has been previously reported in Peru, and appears to predispose to more severe disease and coinfection with multiple pathogens, as seen with our patient (https://www.ncbi.nlm.nih.gov/pubmed/20560735). Unfortunately, testing for HTLV is not widely available in Cusco and the patient could not be tested.

The more common presentation is chronic paracoccidioidomycosis (CoW 2017-08, 2013-05), seen in adults between 40 and 60 years of age. Patients initially present pulmonary manifestations such as cough and dyspnea, and are often misdiagnosed with tuberculosis. Later symptoms include granulomatous or ulcerated mucocutaneous lesions (especially in mouth and nasopharynx), and occasionally central nervous system involvement. Acute or juvenile paracoccidioidomycosis is an uncommon form and it is typically seen in children, adolescents and immunosuppressed adults (CoW 2010-07, 2006-02). It presents with fever, anorexia, asthenia and malaise. Respiratory and mucocutaneous manifestations are not regularly seen. Because of rapid dissemination of the pathogen to the reticuloendothelial system, physical examination often reveals generalized adenopathies, subcutaneous nodules, hepatosplenomegaly, and sometimes bone involvement. Differential diagnoses for this clinical presentation of Paracoccidioides spp. infection include histoplasmosis, tuberculosis, syphilis, and lymphoma.

The treatment of choice for most cases of paracoccidioidomycosis is itraconazole at doses of 100-200 mg/day. In patients with severe disease or central nervous system involvement, treatment should be started with amphotericin B deoxycholate, and can be switched to an oral agent after clinical improvement. Treatment should be continued until there is substantial clinical and radiological evidence of improvement or resolution of symptoms, usually after 6 to 12 months. About 5% of patients may relapse, especially if they had disseminated disease (https://www.ncbi.nlm.nih.gov/pubmed/18380607). Our patient received a course of treatment with albendazole, and is currently receiving amphotericin B deoxycholate, with moderate improvement.

Regarding the other diagnoses, leishmaniasis is endemic in the area where the patient lives. The most commonly isolated species in the area is L. braziliensis, which raises concerns for mucous membrane involvement. Pentavalent antimonials are the first-choice therapy, but if it is not available, amphotericin B can also be used. After completing treatment, our patient needs to be periodically monitored for relapses - ideally, every three months for at least one year.

Myiasis refers to the infestation of fly larvae in human tissue, and can be primary, if the larvae invades intact skin, or secondary, if it infects damaged skin (as seen with our patient, who had myiasis over a kerion). The most frequently described species in Peru are Cochliomyia hominivorax and Dermatobia hominis (CoW 2004-06, 2005-06, 2008-06). Removal of larvae is curative, although some cases may require antibiotic therapy for bacterial superinfection.

There are two major species of hookworm that may infect humans: Ancylostoma duodenale, in Europe and Asia, and Necator americanus, in the Americas, Africa, and some parts of Asia. Their eggs are indistinguishable. Infection with hookworm may cause cutaneous larva migrans upon dermal penetration of the parasite, some coughing and pharyngeal irritation as the parasite passes through the lungs, and nausea, vomiting, diarrhea, or abdominal pain when the larvae migrate to the small intestine. Chronic infection may cause anemia due to blood loss when the worms attach to the intestinal mucosa. Diagnosis is made by observation of eggs on stool examination; the standard method is the Kato Katz technique. Treatment consists of albendazole 400mg daily for three days; alternatives include mebendazole and pyrantel pamoate. Single doses of albendazole are used in public health programs. There is scant evidence about the benefit of regular deworming of groups at risk without evidence of infection (https://www.ncbi.nlm.nih.gov/pubmed?term=26202783).

University of Alabama at Birmingham

Gorgas Case 2020-05

Universidad Peruana Cayetano Heredia
The following patient was seen as an outpatient at Cayetano Heredia Hospital during the Gorgas Diploma Course.
Image for Case 2020-05

History: A 65-year-old man presented to the infectious disease clinic with a 6-year history of illness characterized by a cutaneous ulcer on the left forearm, for which he unsuccessfully received multiple courses of treatment at other medical providers with 1) pentavalent antimonials for suspected cutaneous leishmaniasis and 2) standard anti TB drugs after a skin biopsy showed a granulomatous reaction.

Epidemiology: Born in San Martin, lives in Ucayali, both in the low jungle of Peru. Works in agriculture. Denies contact with known TB patients. Past medical history is remarkable for type 2 diabetes mellitus, treated with metformin for the past 10 years.

Physical Examination: On the left forearm, a slightly elevated verrucous plaque with an atrophic center, peripheral desquamation and numerous black dots (Image A). The rest of the physical exam was unremarkable.

Laboratory: Hb:15.4 g/dL, Hct 46%; WBC 7.48 (bands: 0%, neutrophils: 47.1%, eosinophils: 18%, basophils: 0.4%, monocytes: 6%, lymphocytes: 27.8%); Platelets: 273 000. Glucose: 121, Urea: 27 mg/dL, Creatinine: 0.79 mg/dL, AST: 48 U/L, ALT 42 U/L, Alk phos: 164 UI/L.

UPCH Case Editors: Carlos Seas, Course  Director / Alvaro Schwalb and Paloma Carcamo, Associate Coordinators
UAB Case Editors: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director


Diagnosis: Chromoblastomycosis

Images for Case 2020-05
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Discussion: Microscopic examination of skin scraping revealed abundant muriform cells on direct examination (Image B), and a diagnosis of chromoblastomycosis was made. Skin biopsy confirmed this, showing pseudoepitheliomatous hyperplasia in the epidermis and chronic granulomatous inflammation with suppurative foci underneath, with structures resembling dematiaceous fungi. Fungal cultures for speciation are pending.

Diagnosis is best made by direct microscopy using KOH of skin scrapings taken from areas of the lesion with abundant black dots, which reveals muriform or sclerotic bodies - pathognomonic for chromoblastomycosis. Skin biopsy (which should include black dots as well) also reveals muriform bodies, along with signs of pyogranulomatous inflammation (Image C). Muriform bodies are usually seen as an aggregation of 2-4 round brownish thick-walled 4-12 μm structures with transverse and longitudinal septation. Occasionally, dematiaceous hyphae may also be seen. Fungal culture must be performed in order to identify species; oftentimes molecular biology techniques such as PCT are needed to complete work-up.

Chromoblastomycosis is a chronic subcutaneous mycosis caused by inoculation of spores from dematiaceous fungi. It is prevalent in Southern Africa and parts of Latin America, including Mexico, Brazil and Venezuela. However, it has also been reported in countries with temperate climates. In Peru, sporadic cases have been reported in Ucayali and Cusco (https://onlinelibrary.wiley.com/doi/abs/10.1111/ijd.13665).

It is typically caused by two genera of dematiaceous (also known as melanized or phaeoid) fungi: Cladophialophora and Fonsecaea, both found in tropical rainforests. About 90% of isolated species are identified as Fonsecaea pedrosoi (http://www.scielo.br/scielo.php?pid=S0365-05962018000400001&script=sci_arttext). They are typically isolated from soil and plants, thus farm workers and gardeners are at higher risk of infection.

Chromoblastomycosis presents with an initial papule with centrifugal growth that may evolve into different clinical forms. The verrucous-type lesion, as seen in our patient, is the most prevalent. These types of lesions are hyperkeratotic and warty in appearance, have a high fungal load, and ulcerate easily. Another type of lesion is the nodular type, with fibrotic, red-violet nodules with a smooth or hyperkeratotic surface. Plaque-type lesions can also be red or violet, and are usually well circumscribed although irregular in shape, with sharp, elevated edges. The tumoral-type lesions can be single or multiple and coalescent, and can be either smooth or scaly. Cicatricial-type lesions can have an annular, serpiginous, or irregular configuration, and usually grow centrifugally. Metastatic lesions may appear by contiguous spread, hematogenous or lymphatic dissemination. Lesions are more frequently found in lower limbs, but can appear anywhere on the body. All of the forms typically have a “cayenne pepper” appearance, as seen in Image A. The black dots represent transdermal elimination of fungal debris. Patients are usually oligosymptomatic, presenting only mild pruritus and sometimes local pain, and take a long time to seek medical attention. (http://www.scielo.br/scielo.php?pid=S0365-05962018000400001&script=sci_arttext)

The differential diagnosis for a verrucous plaque such as the one seen in our patient includes cutaneous tuberculosis, non-TB mycobacterial infections, sporotrichosis, leishmaniasis, leprosy and lobomycosis. Non-infectious diagnoses such as sarcoidosis or cutaneous malignancies must also be ruled out.

Treatment is difficult, with low cure and high relapse rates, and there is no high-grade evidence to support it. Therapy choice depends on disease severity. Mild disease, defined as a solitary plaque or nodule less than 5 cm in diameter, should be treated with surgical excision, which can be curative. Cryotherapy and thermotherapy may also be considered. However, since most patients seek medical care late in the course of the disease, this is not often an option. Moderate disease includes single or multiple lesions with nodular, verrucous or plaque morphology, less than 15cm in diameter, and involving up to two adjacent skin areas. Severe disease occurs when there is extensive involvement. For moderate to severe disease, extended regimens of oral antifungals are recommended. The agents with greatest proven efficacy are itraconazole and terbinafine, given for 6-12 months at high doses, with similar cure rates of 15-80% (https://www.ncbi.nlm.nih.gov/pubmed?term=27856522). In cases of resistance to standard antifungals, posaconazole has shown good clinical success rates (https://www.ncbi.nlm.nih.gov/pubmed/16553324).

Complications of chromoblastomycosis include tissue fibrosis that may lead to lymphatic blockage and stasis, bacterial superinfection, or even development of malignancy. Some cases of chromoblastomycosis-associated squamous cell carcinoma have been reported (https://www.ncbi.nlm.nih.gov/pubmed?term=25681378).

Our patient is currently in his third month of treatment with oral itraconazole, with slow improvement of the lesion.


University of Alabama at Birmingham

Gorgas Case 2020-04

Universidad Peruana Cayetano Heredia
The following patient was seen in the surgical intensive care unit at Hospital Cayetano Heredia during the Gorgas Diploma Course.
Image for Case 2020-04

History: A 60-year-old male patient presented to the hospital complaining of 10 weeks of fever, night sweats and weight loss. 8 weeks before admission, he presented to a local physician with mild diffuse abdominal pain, and watery diarrhea, and is treated with ciprofloxacin for 7 days, with remission of the diarrhea. Over the next 2 weeks, he develops anorexia and asthenia, accompanied by worsening abdominal pain. He is treated with ivermectin, but his symptoms show no improvement. A month prior to admission, he starts noticing dyspnea, which steadily progresses and by the day of admission to the Tropical Medicine ward is present at rest.

Epidemiology: Born and lives in Moyobamba, San Martin (tropical jungle of Peru). Worked as a farmer until 2005 but is currently unemployed. Raises chickens around his house and also has dogs. Past medical history includes cryptococcal meningitis in 2008. The patient denies other past illnesses and surgeries. No known TB contacts.

Physical Examination: BP: 90/70 mmHg; RR: 24; HR: 116; T: 38°C. Presented with marked pallor; no rash or petechiae. No mucosal lesions. Palpable bilateral inguinal lymphadenopathy, about 3cm in diameter. Pulmonary exam revealed bilateral diffuse crackles. Cardiovascular exam was unremarkable. Abdomen was not distended but slightly tender to palpation, liver span ±15cm, no splenomegaly. Patient was alert, oriented, with no focal deficits, and no meningeal signs.

Imaging Studies: CXR revealed bilateral interstitial infiltrates (Image A). Thoracic CT showed interstitial infiltrates in both inferior lobes and the left superior lobe, with bilateral bronchiectasis and mediastinal lymphadenopathy(Image B). Abdominal CT revealed discrete hepatomegaly.

Laboratory: Hb 8.9 g/dL; Hct 28%; WBC 4.64 (bands 0%, neutrophils 71.1%, eosinophils 1.3%, basophils 0.2%, monocytes 9.3%, lymphocytes 16.8%); Platelets 163 000. Gluc 103 mg/dL, Urea 37 mg/dL, Creat 0.7 mg/dL, Na 133 mEq/L, K 3.57 mEq/L, Cl 99 mEq/L, Total bilirubin 0.3 mg/dL, Indirect bilirubin 0.2 mg/dL, Alk phos 169, AST 108, ALT 50, GGT 107, LDH 291 (N=???), CRP 197.7, HIV and HTLV non-reactive. Blood cultures x2: negative. AFB, GeneXpert MTB/RIF, culture in BAL for bacteria and mycobacteria: negative.

UPCH Case Editors: Carlos Seas, Course  Director / Alvaro Schwalb and Paloma Carcamo, Associate Coordinators
UAB Case Editors: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director


Diagnosis: Progressive disseminated histoplasmosis

Images for Case 2020-04
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Discussion: A transbronchial lung biopsy revealed chronic granulomatous infiltration with some giant multinucleated cells; Ziehl-Neelsen and Grocott stains were negative for AFB and fungi (Image C). Bone marrow culture was positive for Histoplasma capsulatum, showing multiple macroconidia stemming at right angles from the parent hyphae (Image D). Bone marrow biopsy showed a granulomatous reaction with no evidence of malignancy. Image E shows the typical 7-10 μm H. capsulatum tuberculated macroconidia, after 30 days of growth. Urine histoplasma antigen was positive as well.

H. capsulatum is a dimorphic endemic fungus of worldwide distribution, most commonly reported in the Americas. It has been estimated to have an incidence of less than 0.1 per 100 000 inhabitants in Peru (https://www.ncbi.nlm.nih.gov/pubmed/28188491). H. capsulatum has been isolated from pigeon droppings in Lima, the country’s capital, (https://repositorio.cientifica.edu.pe/handle/UCS/436), and from the soil in caves in Tingo María, in the tropical Peruvian jungle, which has been linked to histoplasmosis outbreaks in tourists (http://www.scielo.org.pe/scielo.php?pid=S1726-46341955000100003&script=sci_arttext). It is presumed to be endemic in all of the Peruvian jungle. Infection occurs through inhalation, and has been linked to occupational and recreational activities that disrupt soil or bird and bat droppings, such as, in the case of our patient, agriculture.

Although exposure to H. capsulatum is very common in endemic areas, as is evidenced by high cutaneous histoplasmin positivity rates, overt clinical manifestations occur in less than 1% of infected people. The most common manifestation is acute pulmonary histoplasmosis, a self-limited illness that presents with fever, malaise, headaches, and weakness. Nonetheless, patients with immunosuppression may present with disseminated disease. Upon infection, most patients have asymptomatic hematogenous dissemination through parasitized macrophages and, although, immunocompetent hosts are able to control the infection through T-lymphocyte mediated macrophage activation, they may still retain foci of H. capsulatum in various organs which can reactivate if there is altered immunity. Thus, even patients who have not been in endemic areas for many years may present the disease.

Disseminated histoplasmosis is mostly seen in immunocompromised patients (HIV, patients on corticosteroids or biological therapy, extremes of ages), however, it has also been reported in patients with no identifiable risk factors. In the setting of a patient with disseminated histoplasmosis with no clear cause of immunosuppression, experts recommend further study of immune status, i.e lymphocyte and immunoglobulin studies.

The disease typically presents with malaise, anorexia and weight loss. Physical exam may reveal hepatosplenomegaly, lymphadenopathy, pallor, and mucocutaneous ulcers, nodules or papules. Laboratory studies may show non-specific alterations such as elevated alkaline phosphatase, pancytopenia, and elevated inflammatory markers. Gastrointestinal compromise is frequent, presenting with abdominal pain and diarrhea, though most cases are asymptomatic. Suprarenal glands are often affected, causing fever, malaise, orthostatic hypotension, nausea, vomiting, and electrolyte abnormalities. Mucosal involvement is frequent, with ulcerations in tongue, gingival and buccal mucosa, lips, pharynx, and larynx. Every organ system can be affected, but many are rarely symptomatic.

The diagnosis of disseminated histoplasmosis is made by microscopic evidence or isolation of H. capsulatum from extrapulmonary sites. Cultures may be drawn from the blood, lungs, bone marrow, or any other suspected site, and are the gold standard for diagnosis, but take a long time to grow. Fully formed macroconidia, as seen in the images for this case, are only seen after 30 days. Cultures typically have a higher yield in patients with disseminated disease. Biopsies from affected organs often reveal typical 2-4 μm intracellular yeasts with a narrow base budding, best seen with PAS or methenamine silver stains. Rapid diagnosis can be achieved by means of antigen detection by enzyme immunoassay in urine, serum, cerebrospinal fluid or bronchoalveolar lavage. Urine antigen testing is positive in about 75% of immunocompetent patients and 95% of immunocompromised patients with disseminated histoplasmosis, but may be falsely positive in the setting of infection with other endemic mycoses (https://www.ncbi.nlm.nih.gov/pubmed/21810734). Serologic testing is most useful for subacute and chronic forms of infection, as antibodies become detectable after 4-8 weeks of infection. However, positive serology only indicates exposure to the fungus at some point and is of little use in endemic areas, where most people have been exposed.

The differential diagnosis for a patient presenting with a long history of fever, lung and abdominal involvement must include tuberculosis, especially in endemic areas such as Peru. The clinical presentation of TB may be indistinguishable from that of disseminated histoplasmosis. Molecular testing for tuberculosis has a relatively high sensitivity and specificity —GeneXpert MTB/RIF in bronchoalveolar lavage has a sensitivity of 80% and a specificity of 98% (https://www.ncbi.nlm.nih.gov/pubmed/29964143), which helps to narrow down the diagnosis. Endemic mycoses such as cryptococcosis or talaromycosis (in the right endemic setting) should also be considered in the differential diagnosis; as for non-infectious differential, also include malignancy and other inflammatory diseases such as sarcoidosis.

Treatment is warranted in all cases of disseminated histoplasmosis, as the natural history of this form of infection is almost invariably fatal. Patients with severe disease should be initially treated with a lipid formulation of amphotericin B, which quickly eradicated fungemia and has more easily titratable serum levels than itraconazole. If there is a good response, after one or two weeks and if there is no fever and good oral tolerance, patients can be switched to itraconazole. Fluconazole, posaconazole and voriconazole may be used if itraconazole is not tolerated, but these agents have not been as well studied. Treatment should be continued for at least a year, to reduce the risk of relapse (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1797635/).

Our patient was empirically started on amphotericin B and the standard anti-tuberculosis regimen. When cultures came back positive for H. capsulatum, tuberculosis drugs were suspended and amphotericin B continued. Further testing revealed a CD4 count of 37/uL (18%) and CD8 count of 145/uL (72%), with a CD4/CD8 of 0.26. Unfortunately, he did not respond well to treatment and succumbed to the infection.

University of Alabama at Birmingham

Gorgas Case 2020-03

Universidad Peruana Cayetano Heredia
The following patient was seen as an outpatient in the Infectious Disease Department of Hospital Cayetano Heredia during the first and second week of the Gorgas Diploma Course.
Image for Case 2020-03

History: A 27-year-old male patient complains of 3 months of ulcerative lesions on the left forearm and nuchal region. The lesions began as small, pruritic, erythematous papules, both of which ulcerated over about two weeks. He was seen by a dermatologist and treated with oral cefradine and topical fusidic acid for 7 days, followed by oral ciprofloxacin and clindamycin for an additional 7 days, without improvement. He noticed the appearance of multiple new painless ulcers on his shoulders and back and presented to our institution.

Epidemiology: He works as a botanist. Two months before symptom onset, he traveled to La Convencion, Cusco (tropical jungle) to work on an environmental impact study, where he camped outdoors, bathed in rivers and got many arthropod bites. The next month, he traveled for work to Loreto (tropical jungle) for a month under similar conditions. He denies any previous illnesses or contact with TB patients. No other colleagues had presented with similar symptoms.

Physical Examination: BP: 120/80 mmHg; RR: 16; HR: 65; afebrile. 18 different skin ulcers (as pictured in Images A and B) on the face, neck, torso, arms, legs, and genitals. The skin lesions pictured are painless ulcers with elevated borders, with the center covered in white-yellow fibrinous material. The rest of the physical exam was unremarkable.

Laboratory: Hb:14.8 g/dL; WBC 8.85 (bands: 0%, neutrophils: 53%, eosinophils: 2%, basophils: 0%, monocytes: 6%, lymphocytes: 39%); Platelets: 302 000. Urea: 44 mg/dL, Creatinine: 1.04 mg/dL, AST: 22 U/L, ALT 20 U/L, HIV: non-reactive.

UPCH Case Editors: Carlos Seas, Course  Director / Alvaro Schwalb and Paloma Carcamo, Associate Coordinators
UAB Case Editors: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director


Diagnosis: Disseminated cutaneous leishmaniasis

Images for Case 2020-03
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Discussion: Image C is typical of new world leishmaniasis. Microscopy of a skin scrapings with Giemsa staining revealed numerous Leishmania sp. amastigotes (Image D). A leishmanin skin test (LST) was positive. PCR for Leishmania sp. speciation was not available.

About 74% of Peru is endemic for leishmaniasis, which is transmitted by the bite of the female sandfly: Phlebothomus sp. for Old World Leishmaniasis and Lutzomyia sp. for New World Leishmaniasis. Two forms are typically described. The Andean form, commonly known as “uta”, occurs on the western slopes of the Andes at altitudes between 900 and 3000 meters above sea level and are usually caused by L. peruviana. The Sylvatic form, or “espundia”, occurs in the tropical jungle and is usually caused by L. braziliensis. Other species that have been identified in the Peruvian territory include L. guyanensis, L. lainsoni, L. amazonensis, and L. shawi (https://www.ncbi.nlm.nih.gov/pubmed/9715953, https://www.ncbi.nlm.nih.gov/pubmed/31220120). In 2018, the Ministry of Health reported 6022 cases of leishmaniasis, of which 92.5% was cutaneous and 7.5% was mucocutaneous (https://www.dge.gob.pe/portal/docs/vigilancia/sala/2019/SE07/leishmaniosis.pdf)

The clinical manifestations of leishmaniasis are diverse and are influenced by the infecting species. Localized cutaneous leishmaniasis presents as one or a few characteristic lesions, as described above, with a positive LST. In Peru, it is typically caused by L. peruviana and L. amazonensis. Mucocutaneous leishmaniasis, as the name states, involves mucosal membranes and may be disfiguring. Most cases with mucosal involvement in Peru are related to L. braziliensis, which typically start as cutaneous lesions that later progress, often years after resolution of the primary lesions, destroying mucosal tissue. Diffuse cutaneous leishmaniasis, a rare form of the disease, presents as multiple nodular lesions that do not form ulcers, and is characteristically associated with anergy, with a negative LST (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486117/).

Our patient had a clinical form of leishmaniasis known as disseminated leishmaniasis which was first described in patients from the northeastern region of Brazil (https://www.ncbi.nlm.nih.gov/pubmed/12447770?dopt=Abstract). Patients present with an initial ulcerated lesion, that erupts into multiple pleomorphic lesions within 2-6 weeks, with no further exposure to the parasite from subsequent mosquito bites. Patients may present non-specific systemic symptoms such as fever, asthenia, or nausea. The lesions may be acneiform, papular, nodular, or ulcerated, ranging from dozens to hundreds. Lesions are found in two or more non-contiguous areas of the body, and commonly involve mucosal membranes (in up to 53% of cases) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360961/). This clinical form seems to stem from a complex interaction between host and parasite factors. Peripheral blood lymphocytes from patients with disseminated disease seem to produce lower levels of Th1 than in patients with localized disease, but immune function at the lesion site is preserved. On the other hand, L. braziliensis isolated from patients with disseminated leishmaniasis have a higher production of TNF and INFγ than isolates of the same species from patients with localized disease (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486117/).

In patients presenting with disseminated cutaneous lesions, the differential includes other infections such as cutaneous histoplasmosis, paracoccidioidomycosis, myiasis, and tuberculosis, which are all endemic in Peru. In other parts of the world, one might also consider talaromycosis and eschars of scrub typhus. However, for all of the conditions mentioned, one would have to look for coexisting immunosuppressive conditions (HIV infection, use of biological therapy), which was not the case for our patient.

The diagnosis of disseminated leishmaniasis relies on clinical characteristics, and laboratory confirmation is based on the identification of the parasite by direct observation, culture, PCR or histopathology. Lesions typically have a large number of amastigotes and are easily identifiable in skin scrapings. Skin scrapings are preferred over punch biopsies because they are rapid, non-invasive and require less expertise. In this type of sample, amastigotes might be seen outside macrophages (as seen in Image D), unlike in skin biopsies. LST is positive in up to 83% of cases (https://www.ncbi.nlm.nih.gov/pubmed/21723576/). Also called Montenegro test, LST is an immunologic skin test that measures delayed-type hypersensitivity (DHT) to Leishmania antigen; it is not available in most countries. Intradermal injection of killed promastigotes will induce a DHT reaction in individuals with current or prior exposure to Leishmania. Injection site is examined 48 hours later and an induration of ≥ 5 mm is considered positive.

Disseminated leishmaniasis is a challenge to treat, and has low cure rates (23%). Pentavalent antimonials are the first-choice therapy, but patients typically require more than one course of treatment or switching to amphotericin B (http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0365-05962019000100002). Liposomal amphotericin B has shown promising results for treatment of this condition, with cure rates around 80-90% and more tolerable side effects, but is expensive and difficult to obtain in Peru. Our patient is currently receiving a course of amphotericin B deoxycholate for a total cumulative dose of 25mg/kg, showing moderate improvement of skin lesions. Due to its toxic effects, the patient is being administered the treatment every other day. After course completion, the patient will be seen at the outpatient clinic in order to evaluate the need for further treatment courses.


University of Alabama at Birmingham

Gorgas Case 2020-02

Universidad Peruana Cayetano Heredia
The following patient was seen in the Internal medicine ward of Cayetano Heredia Hospital during the first and second week of the Gorgas Diploma Course.
Image for Case 2020-02

History: A 57-year-old male patient presented to the ER with a 2-week history of illness that started when he was accidentally grazed by exploding fireworks fragments on his left cheek. He was taken to a local health center, where the wound was cleaned and sutured. On the fifth day after the accident, he noted swelling and redness around the wound with scanty purulent discharge. On probing, a piece of cardboard came out of the wound. He also noticed difficulty opening his mouth. During the ensuing days, this symptom became more severe until he noted difficulty in chewing and swallowing, and rigidity in the neck, which spread to the upper back, so he decided to travel to Lima to seek specialized medical attention.

Epidemiology: He is originally from Puño, Huanuco, a central Andean region of Peru, where he still resides working as a farmer. The patient denies any past medical or surgical history. He has not received any vaccinations during his life.

Physical Examination: BP: 116/74 mmHg; RR: 19; HR: 76; T: Afebrile. The patient was brought in a wheelchair with the facial expression pictured in Image A. He had a linear scar with a necrotic center in his left cheek with surrounding erythema, but no apparent discharge. The musculoskeletal examination revealed contraction of neck, upper dorsal and masseter muscles. Pulmonary, cardiovascular and abdominal exams were unremarkable. The patient was alert, GCS 15/15, and muscular strength was preserved in the four extremities. Kernig and Brudzinski signs were negative. Cranial nerve examination revealed no further abnormalities.

Laboratory: Hb: 17.5 g/dL; WBC 8.80 (bands: 0%, neutrophils: 63%, eosinophils: 0.9%, basophils: 0.2%, monocytes: 7.4%, lymphocytes: 27.7%); Platelets: 421 000. Gluc: 102 mg/dL, Urea: 46 mg/dL, Creat: 0.9 mg/dL, CPK: 418 U/L, CRP: negative. Wound swab culture: negative for aerobic organisms.

UPCH Case Editors: Carlos Seas, Course  Director / Alvaro Schwalb and Paloma Carcamo, Associate Coordinators
UAB Case Editors: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director


Diagnosis: Localized tetanus

Images for Case 2020-02
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Discussion: Based on the patient’s history and physical exam findings, a clinical diagnosis of tetanus was made. Tetanus, also known as “lockjaw”, is usually confined to developing countries and is the cause of about 10,000 deaths worldwide every year, despite being vaccine-preventable. Up to 60% of cases are neonatal and related to contamination of the umbilical stump, but the disease may also be seen in children and adults, associated with lacerations of hands and feet.

Clostridium tetani, the causative agent of this disease, is a strictly anaerobic ubiquitous Gram-positive bacillus. Some strains of C. tetani produce an exotoxin, tetanospasmin, which enters the nervous system through the myoneural junction from adjacent muscles, and can also disseminate through blood or lymph (https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/tetanus.pdf). In order for the C. tetani spores to germinate and multiplicate, they must be inoculated into damaged tissue, usually with soil or other bacteria. However, it has been described that some 7% of tetanus cases may present without a point of entry (https://www.ncbi.nlm.nih.gov/pubmed/9752941).

Clinical manifestations are a consequence of the effects of tetanospasmin. There is increased muscle tone due to blockage of the inhibitor impulses of motor neurons which causes unopposed and painful intense muscle contractions. The incubation period usually ranges from 3 to 21 days, followed by progression to muscle spasms, usually within 24 to 72 hours. The first symptom is usually contraction of masseter muscles and trismus, due to the shorter length of the muscles’ axons. Three different forms of tetanus have been described. Local tetanus presents as a localized contraction of muscles in the surrounding area of the initial injury and is very rarely described. Cephalic tetanus is also rare, presenting with cranial nerve involvement after C. tetani otitis media or injuries to the head. Generalized tetanus is the most common form, presenting with a descending pattern that starts with trismus, then neck stiffness, difficulty swallowing, and rigidity of abdominal muscles. Sustained contraction of muscles in the face can cause a characteristic facies known as risus sardonicus, as seen in our case (Image A). Patients with severe spasticity may present opisthotonus (Case 10-2011, Image B), an extreme arched pose of the head, neck and spinal column caused by spasm of muscles around the spinal column. Our patient presented with a localized form: he only presented rigidity in the muscles close to the site of inoculation. No backward arching of the spine or contractions in the abdomen or upper and lower extremities occurred to indicate generalized tetanus.

The diagnosis of tetanus is clinical, as there are no characteristic laboratory or imaging findings. Only in about 30% of cases can C. tetani be isolated from the wound, although the bacteria can also be found in patients who do not have tetanus, and, as mentioned previously, not all patients will have an obvious point of entry. Other conditions that may also present with trismus include diphtheria, parotiditis, and retropharyngeal or tonsillar abscesses. Oral infections such as these will often present with fever and local pain, which helps differentiate them from tetanus. However, tetanus might also present with fever, if there is an infected portal of entry. Mandibular fractures and temporomandibular arthritis may also present with limited movement of the mouth, but careful history-taking should help discriminate between these conditions. The differential diagnosis for generalized tetanus includes varied conditions such as bacterial meningitis, hypocalcemia, rabies, strychnine poisoning, retroperitoneal hemorrhage, and spondylitis. History and meticulous physical examination are usually enough to rule these conditions out.

The severity of the disease closely correlates with time to onset of symptoms. The Tetanus Dakar score assigns one point for each of the following: time from wound to appearance to first symptom less than seven days, time from first symptom to first generalized spasm less than 48 hours, high-risk point of entry (IM injection, burns, surgery, gynecological, compound fracture, omphalitis), generalized tetanus, core temperature higher than 40°C, heart rate higher than 120/minute. A score of 0-1 is classified as mild, with a mortality of less than 10%, whereas a score of 5-6 is very severe, with a mortality rate higher than 50%. This enables the clinician to weigh the necessity of interventions such as ICU admission or tracheostomy, which is particularly useful in resource-limited settings. Other scores, such as the Tetanus Severity Score, have a better sensitivity and specificity for tetanus-associated mortality, but may be more complex to apply (https://www.ncbi.nlm.nih.gov/pubmed/16553907). Our patient had a mild form of tetanus, as judged by both scores, and his risk of mortality was low.

The initial step in management is to secure the airway. Tracheostomy is warranted in cases of severe tetanus or moderate tetanus with high risk of progression, pharyngeal or laryngeal spasm, hypoxemia or cyanosis, or if the patient requires heavy sedation. Patients should receive benzodiazepines at high doses to control muscle spasms. The current recommended therapy is diazepam at doses of 15-100mg/h, depending on disease severity, and can be combined with chlorpromazine. The IV presentation of diazepam contains propylene glycol, which can cause metabolic acidosis, so patients should be switched to oral diazepam as soon as possible. Due to this drug’s propensity to cause withdrawal reactions, midazolam and lorazepam are being studied as alternatives for long term sedation, but there is scant substantial evidence to support their use (https://pdfs.semanticscholar.org/56f3/7b127b1ad0b5cc3b95e389eeedddb19bd848.pdf). Some studies have suggested that magnesium sulphate could be used both to reduce spasms and to improve autonomic dysfunction, but evidence is still insufficient, especially for severe cases (https://www.ncbi.nlm.nih.gov/pubmed/23033859). An alternative is to combine magnesium sulphate and diazepam. Human tetanus immunoglobulin should be promptly administered to neutralize unbound toxins and prevent further symptom progression. Immunoglobulin is traditionally administered intramuscularly in the shoulder, in a single IM dose. Some guidelines recommend a dose of 3000-6000 IU; however, experts recommend using 500 IU, which appears to be equally effective. There is no apparent benefit in administering immunoglobulin around the point of entry. When human immunoglobulin is not available, equine antitoxin may be used (https://www.ncbi.nlm.nih.gov/pubmed/23949453). Several studies have shown that intrathecal administration of either human immunoglobulin or equine antitoxin may reduce muscular spasms and shorten hospital stays, with varied effects on mortality and need for mechanical ventilation. The administered product should not contain thimerosal, as this may cause arachnoiditis (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4057067/). Patients should receive active immunization upon diagnosis, as tetanus does not confer lifelong immunity. Finally, necrotic tissue and foreign bodies must be removed from the point of entry to prevent further production of toxins, and patients must be started on adequate antibiotics (metronidazole is preferred; penicillin is not recommended because it is an antagonist of gamma amino butyric acid, the inhibitory neurotransmitter) (https://www.ncbi.nlm.nih.gov/pubmed/21357910). There are no specific recommendations for treatment of localized tetanus. Recovery usually takes about 4 weeks, when new synapsis form.

Due to our patient’s vaccination history and the fact that he had a contaminated wound, he should have received both the vaccine and immunoglobulin for prevention of tetanus right after his injury, as per CDC recommendations. Patients with clean wounds but unknown vaccination history or less than 3 doses of Tdap or Td should also be vaccinated (https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/tetanus.pdf).

Our patient was admitted to the Intensive Care Unit, where he received treatment with 3000 IU of intramuscular human anti-tetanus immunoglobulin. He was also treated with metronidazole, diazepam, baclofen and the tetanus toxoid vaccine. He did not require high doses of benzodiazepines, and after a marked improvement in muscular rigidity, he was transferred to the internal medicine ward and discharged shortly after. On his follow-up appointment after discharge, he still felt some stiffness around the mouth but had no trouble swallowing.


University of Alabama at Birmingham

Gorgas Case 2020-01

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 20th consecutive year, we are pleased to share interesting cases seen by the participants that week during the February/March course offerings. Presently the 9-week Gorgas Course in Clinical Tropical Medicine is in session. New cases will be sent by e-mail every Tuesday/Wednesday for the next 9 weeks. Each case includes a brief history and digital images pertinent to the case. A link to the actual diagnosis and a brief discussion follow.
Carlos Seas and German Henostroza
Course Directors
The following patient was seen in the outpatient clinic of the Infectious Diseases Department of the Hospital Cayetano Heredia during the Gorgas Diploma Course.
Image for Case 2020-01

History: A 53-year-old male patient presented to the ER with a 6-day history of headache, myalgia, sweats and fever (cold shivering, then felt hot and exhausted) at the same time every night. He noticed slight jaundice in the face and sclerae, as well as dark urine, on the third day of illness. Additionally, he presented myalgia, predominantly in the lower extremities, which intensified causing difficulty walking. On the day of admission, he presented nausea and vomiting.

Epidemiology: He is originally from Venezuela but migrated to Lima two years ago. One month prior to symptom onset, he was working as a construction worker in Tumbes, in northern Peru. Symptoms started on the last day of the trip. He denies any previous illnesses or surgeries. Unsure if has received yellow fever vaccine. Denies exposure to freshwater. Reports regularly eating from street vendors. Denies risk factors for sexually transmitted infections.

Physical Examination: BP: 80/60 mmHg; RR: 26; HR: 75; T: Afebrile. Patient in no acute distress. Marked pallor, dry mucous membranes, no mucosal petechiae, no jaundice, normal capillary refill. No rash or petechiae. No lymphadenopathy. Pulmonary and cardiovascular exams within normal limits. Abdomen had diminished bowel sounds, distended, liver was palpable 2cm below ribs, spleen was not palpable, tenderness on palpation in left hemiabdomen. Patient was awake, oriented, Glasgow Coma Scale 15/15, no focal deficits, no meningeal signs.

Imaging Studies: Normal CXR on admission.

Laboratory: Hb:12.6 g/dL; Hct. 26%; WBC 4.01 (bands: 8%, neutrophils: 64.1%, eosinophils: 11%, basophils: 0.2%, monocytes: 3%, lymphocytes: 13%); Platelets: 28 000. Gluc: 148 mg/dL, Urea: 44 mg/dL, Creat: 1.5 mg/dL, Na: 139 mEq/L, K: 4.44 mEq/L, Cl: 102 mEq/L, Total bilirubin 2.6 mg/dL, Indirect bilirubin 1.9 mg/dL, Alk phos 144, AST 101, ALT 94, GGT 124, CRP 74.29, HIV non-reactive. Urinalysis was unremarkable. Arterial blood gases: pH 7.42, PCO2 31, PO2 100, HCO3 22, Lactate 2.3 Thin smear is presented in Images A and B.

UPCH Case Editors: Carlos Seas, Course  Director / Alvaro Schwalb and Paloma Carcamo, Associate Coordinators
UAB Case Editors: David O. Freedman, Course Director Emeritus / German Henostroza, Course Director


Diagnosis: Malaria - mixed infection with Plasmodium vivax and Plasmodium falciparum

Images for Case 2020-01
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Discussion: P. vivax schizonts and gametocytes (Images A, B) were found on initial thick smear. There was concern for severe malaria due to the patient’s presentation, with hypotension, elevation of bilirubin, and altered renal function. One day later, the patient reported shortness of breath, with oxygen saturation to 77%, requiring supplemental oxygen. Chest X-ray showed a new consolidation in right base (Image C). Then, new slides prepared from the same blood samples collected on admission revealed P. falciparum gametocytes (Image D).

"An “Effective” (Hangzhou AllTest Biotech) rapid antigen detection test was positive for P. vivax but negative for P. falciparum. This test contains P. vivax anti-HRP-II and anti-pLDH antibodies and P. falciparum anti-HRP-II antibodies. This rapid test has a reported sensitivity of 95% and specificity of 99% for P. vivax and P. falciparum, when compared to microscopy [Cochrane Database of Systematic Reviews 2014, doi: 10.1002/14651858.CD011431] Discrepancy between the microscopy findings and rapid test results for our patient may be explained by absence of HRP proteins due to pfhrp2 or pfhrp3 deletions in some P. falciparum parasites. Peru has the highest documented levels of such deletions  [PloS One 2010, doi: 10.1371/journal.pone.0008091]. Genetic analysis conducted on 188 P. falciparum samples collected in Peru showed that pfhrp2-negative parasites have multiple origins, and possibly evolved independently [Sci Rep. 2013, doi: 10.1038/srep02797]. Prevalence of this character is highly variable in other parts of the world [WHO, Global Malaria Program 2016].

The differential diagnoses of an acute febrile illness in a patient coming from the north coast of Peru include malaria, dengue, typhoid fever, brucellosis and leptospirosis. When considering dengue, the absence of a rash and the duration of the fever made the diagnosis less likely. Typhoid fever and brucellosis are farther down in the list of differential diagnoses due to the patient’s clinical course. Typhoid does not typically present with thrombocytopenia, whereas brucellosis typically presents with arthralgia. Leptospirosis is usually accompanied by marked jaundice and renal failure.

In Peru, there has been an average of 2,530 cases of malaria reported annually from 2015 to 2019, most of them in the Amazon region [CDC Peru]. Management approach relies on the species identified, resistance to antimalarial drugs, and severity of disease. Oral treatment with artemisinin-based combination therapy (ACT) for 3 days is the recommended first-line treatment against both P. vivax and P. falciparum. In P. vivax infection, a 14-day course of primaquine should be added to prevent recurrence. In Peru, due to a low prevalence of G6PD deficiency, patients are not typically tested prior to treatment with primaquine. If there is concern for severe malaria, intramuscular or intravenous artesunate should be used for at least 24 hours and until patients can tolerate oral therapy, then complete treatment with 3 days of ACT. [WHO 2015]

WHO defines severe malaria as the presence of one or more of the following clinical indicators: deep coma suggestive of cerebral malaria, prostration or generalized weakness with inability to walk, two or more seizures within 24 hours, pulmonary edema, ARDS, shock, significant bleeding. It may also be accompanied by laboratory indicators such as severe malarial anemia (Hct: <20%, Hb: <7g/dL), renal failure (serum creatinine >3mg/dL), hypoglycemia (<40mg/dL), hyperparasitemia (>10%), acidosis and hyperbilirubinemia (serum bilirubin >3.0mg/dL). Progression to severe and fatal disease is largely but not entirely confined to P. falciparum. In the case presented, the patient was judged to be at high risk for progression to severe malaria due to hypotension at presentation and altered renal function tests, serum bilirubin, and lactate. Strictly speaking, he did not fulfill WHO criteria for severe malaria; however, he did not tolerate oral medications at the time of admission, and so was started on IV artesunate, of which he received a total of 3 doses. Afterwards, he received a full 3-day course of oral artesunate-mefloquine, followed by 7 days of oral primaquine.

In Peru, most cases are caused by P. vivax or P. falciparum, with occasional reports of P. malariae. Official Peruvian data report mixed infection in 17 of 54,627 reported malaria cases for 2016 [CDC Peru]. However, studies from malaria endemic regions in Southeast Asia report nested-PCR-detected rates of mixed infection as high as 23.5%, where microscopy methods only detect 0-2.5% [Indian J Med Res 2010; 132:31-5]. Underreporting of mixed malaria infection is frequent, due to limitations in diagnostic methods. It is important to accurately diagnose mixed malaria infections because treatment may need to be altered in order to ensure clearance of parasitemia [Malar J 2011, doi: 10.1186/1475-2875-10-253].

One of the most important, although rare, complications of severe malaria is secondary bacterial infections. Increased risk of bacteremia in children with severe malaria has been previously described [Lancet 2011, doi: 10.1016/S0140-6736(11)60888-X]. Bacteria isolated in malaria patients (usually P. falciparum) include Salmonella (typhi, typhimurium, paratyphi), Staphylococcus aureus, and Escherichia coli [Am J Trop Med Hyg 2018, doi: 10.4269/ajtmh.18-0378, Open Forum Infect Dis 2016, doi: 10.1093/ofid/ofw028]. Our patient was started on IV ceftriaxone and clarithromycin because of the new consolidation on the chest X-ray, with marked clinical improvement over the next days.