Gorgas Case of the Week - 2021 Series

University of Alabama at Birmingham

Gorgas Case 2021-06

Universidad Peruana Cayetano Heredia

The following patient was seen as an outpatient at Cayetano Heredia Hospital in Lima.

Image for Case 2021-06

History: A previously healthy 29-year-old male patient presented to the outpatient clinic with a four-year history of pain in the internal aspect of his left hand and later numbness with clawing of his fingers. Later, he developed similar symptoms on his right hand. He says that “hives” appeared on his legs, waist, and arms, with a slight burning sensation that improved with some drugs (does not remember name) and he noted having nasal congestion. Two years prior to presentation, he noted lesions on the face and ears, and posteriorly, numbness and swelling of the feet and legs. He denied fevers, weight loss, or other systemic symptoms.

Epidemiology: Born and lives in the Amazon Basin. No past medical conditions or surgery.

Physical Examination: HR: 72 bpm, RR: 18 rpm, T: 36.8°C, BP: 110/68 mmHg. Skin and soft tissues: Areas of erythema and diffuse infiltration in face, ears, and trunk (Image A); some papules in chin (Image B). Pitting edema in hands, legs, and feet. Bilateral ulnar nerve thickening. Neuro: Complete clawing of the left hand, ulnar clawing of the right hand (Image C). Bilateral thenar and hypothenar atrophy, predominantly in left side. Decreased muscle strength in both hands, 2/5. Normal strength in the rest of the body. Glove and stocking anesthesia in hands and feet with areas of impaired sensation on forearms and legs. The rest of the physical exam was normal.

Electromyography:
• Sensitive conduction velocity
- Right Median and Ulnar: Absent
- Left Median and Ulnar: Absent
• Motor conduction velocity
- Left Median - wrist: Latency 6,8 ms Amplitude 0,98 mV
- Left Ulnar - wrist: Absent
- Right Common Peroneal – intermaleolar: Absent
Conclusion: Severe distal mixed sensitive and motor polyneuropathy
with a demyelinating pattern, predominantly in upper limbs

Laboratory Examination: Hb: 12.2 g/dL; Hct. 36.8%; WBC 8 700 (neutrophils: 56%, eosinophils: 4%, lymphocytes: 30%); Platelets: 295 000. Glucose: 107 mg/dL (N: 70-110). Urea: 33 mg/dL (N: 15-45). Creatinine: 0.97 mg/dL (N: 0.5-1.2). INR: 1.11. Total proteins: 9.41 g/dL. Albumin: 4.08 g/dL. Globulin: 5.33 g/dL.


UPCH Case Editors: Carlos Seas, Course  Director / Paloma Carcamo, Associate Coordinator

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

 

Diagnosis: Leprosy (Hansen’s Disease). Multibacillary leprosy according to the WHO classification. Probable Borderline Lepromatous according to Ridley-Jopling classification.

Images for Case 2021-06
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Discussion: Slit-skin smears were not performed for this patient. A skin biopsy of the lesions with Fite-Faraco staining revealed abundant acid-fast bacilli (AFB) corresponding to Mycobacterium leprae (Image D).

In patients who present with symptoms that are compatible with leprosy, slit-skin smears should be taken first, as they can be sufficient for diagnosis. Slit-skin smears are performed by making small slits (about 5 mm in length and 2 mm in depth) in pinched skin (to avoid bleeding), and then scraping the edges. Frequently sampled areas include ear lobes, the dorsal surface of the elbows and anterior surface of the knees. The obtained material is smeared on a clean slide, stained for AFB with a modified Ziehl-Neelsen, and examined microscopically. Bacilli can also be found in the nerves, though nerve biopsies are usually reserved for patients with subclinical or primarily neuropathic forms of leprosy. Our patient presented to our institution with the results of a skin biopsy performed elsewhere.

Skin biopsies, though helpful to determine the extent of involvement, are not essential to diagnosis. In fact, the diagnosis of leprosy can be made on the basis of one of three cardinal signs: definite loss of sensation in a pale or reddish skin patch, thickened or enlarged peripheral nerves with loss of sensation or weakness in the corresponding muscles, or presence of AFB in a slit-skin smear. In higher resource settings, PCR-based assays may be used to improve diagnostic accuracy, but they are not necessary for diagnosis. The clinical picture in the presented patient, then, was sufficient to make a diagnosis of leprosy.

Leprosy can present in various clinical forms depending on the host’s immune response, according to the Ridley-Jopling classification [1]. The spectrum of disease ranges from tuberculoid leprosy (TT), in which there are few or no AFB in the lesions and there is good cell mediated immunity, to lepromatous leprosy (LL), in which there are many AFB and poor cell-mediated immunity (as was the case with the presented patient). However, the 2018 World Health Organization (WHO) Guidelines [2] recommend a different classification system, which categorizes cases of leprosy only as paucibacillary or multibacillary in order to guide treatment. Paucibacillary cases present with 1-5 skin lesions, and no bacilli in slit-skin smears. Multibacillary cases have either more than 5 skin lesions, nerve involvement, or demonstrated bacilli in slit-skin smears. These criteria make it easy to discern between the two types of leprosy and determine the best course of treatment even when slit-skin smears and biopsies cannot be performed.

LL typically presents with diffuse infiltration of the skin, and multiple mildly erythematous lesions that may or may not be hypoesthetic; in contrast to TT which presents usually with a single anesthetic macule or plaque. The most commonly affected nerves are the ulnar, median, lateral popliteal, posterior tibial, and facial nerves, which can become enlarged and cause regional patterns of sensory and motor loss. In LL, patients are typically described to have glove and stocking sensory loss due to compromise of small dermal sensory and autonomic nerves. Advanced neuropathies can lead to deformities as were observed in the described patient, including claw hand, footdrop, claw toes, and limb insensitivity, which in turn can lead to more damage due to burns and other daily trauma that goes unnoticed by the patient. Systemic symptoms can result from infiltration of mycobacteria in various anatomic structures [3]. In the presented patient, the nasal congestion could be attributed to infiltration of the nasal mucosa.

Borderline lepromatous (BL) patients present with innumerable small plaques that resemble hives; these lesions are not seen in lepromatous (LL) patients. The fact that this patient had pain and numbness on his hand, with posterior clawing and the presence of mildly burning “hives” suggests that he was having a type 1 reaction which is seen in borderline patients but not in LL patients. So-called type 1 reactions may occur in up to one-third of borderline patients. These reactions consist of inflammation of the skin lesions and/or the peripheral nerves. Clinically, the skin lesions swell up, become more erythematous, shiny, and warm, and new lesions may appear; additionally, the nerves become swollen and painful. Nerve function deterioration follows if untreated. Therefore, we think that these “non-pruritic hives” and the pain on the ulnar aspect of the hand were caused by a type 1 reaction and that this patient is best classified as borderline lepromatous, very close to the lepromatous end of the spectrum. Type 1 reactions are caused by increases in T-cell reactivity to M. leprae with infiltration of reactive CD4 cells into skin lesions and nerves. The edema and painful inflammation must be treated urgently with high-dose steroids in order to prevent further nerve damage. After treatment is completed, some patients may partially recover skin sensation, but longstanding nerve damage is irreversible. When starting therapy for these patients, it is important to warn them about the possibility of developing a type 1 reaction, so that the patient does not stop the therapy for leprosy thinking that it is producing the reaction.

The differential diagnosis for a patient with erythematous infiltrative skin lesions includes cutaneous sarcoidosis, mycoses fungoides, adult T-cell leukemia-lymphoma caused by HTLV-1, diffuse cutaneous leishmaniasis, and scleromyxedema. However, leprosy is unique in that the lesions may have diminished sensory perception, and peripheral nerve involvement is usually found, which is not characteristic of any of the aforementioned conditions.

WHO recommends that treatment be started with a 3-drug regimen of rifampicin, dapsone, and clofazimine. Paucibacillary cases should be treated for 6 months, while multibacillary cases should be treated for 12 months. The US National Hansen’s Disease Program recommends longer courses of treatment to reduce relapses: 12 months of treatment with daily dapsone and rifampicin for patients with paucibacillary leprosy, and 24 months with daily dapsone, rifampicin and clofazimine for patients with multibacillary leprosy. Rifampicin-resistant cases should be treated with at least two second-line drugs (clarithromycin, minocycline, or a quinolone) and clofazimine daily for 6 months, and then one second-line drug plus clofazimine for another 18 months. The possibility of adverse effects of dapsone and clofazimine should be considered, and a reference text should be consulted prior to initiation of therapy by anyone not familiar with these.

This patient will be treated with the multibacillary regimen recommended by WHO. The most common adverse reaction in multibacillary disease, occurring in about 50% of patients with lepromatous and borderline lepromatous leprosy, is a Type 2 reaction, which most commonly presents as erythema nodosum leprosum (ENL). ENL is considered an antigen-antibody immune complex deposition in the tissues, often accompanied by a severe systemic illness, and characterized by high levels of tissue and circulating TNF-α. ENL presents with fever and tender erythematous nodules [4], and may also produce, to varying degrees, neuritis, uveitis, myositis, dactylitis, periostitis, orchitis, lymphadenitis and nephritis accompanied by edema, arthralgia, and leukocytosis. It can occur in patients prior to, during, or after therapy, until the antigen load decreases markedly, and may present as repeated acute episodes or be chronic and ongoing. ENL can be treated symptomatically if mild or with prednisone or thalidomide if severe [see Gorgas Case 2011-04].

With proper treatment, the patient’s skin lesions may resolve within a few years, but the long-standing nerve damage is irreversible, and the resulting deformities will be permanent. Patients with sensitive deficits secondary to leprosy need to be taught to regularly evaluate and properly care for areas of loss of sensation to prevent further damage. They should also exercise extending their fingers to retain flexibility of the contractions.

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


References
1. Britton WJ, Lockwood DNJ (2004) Leprosy. Lancet Lond Engl 363:1209–1219
2. WHO SEARO/Department of Control of Neglected Tropical Diseases (2018) Guidelines for the diagnosis, treatment and prevention of leprosy.
3. Walker SL, Lockwood DNJ (2007) Leprosy. Clin Dermatol 25:165–172
4. Pocaterra L, Jain S, Reddy R, Muzaffarullah S, Torres O, Suneetha S, Lockwood DNJ (2006) Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India. Am J Trop Med Hyg 74:868–879.

 
University of Alabama at Birmingham

Gorgas Case 2021-05

Universidad Peruana Cayetano Heredia

The following patient was seen as an outpatient at a private clinic in Lima.

Image for Case 2021-05

History: A 25-year-old male patient was initially transferred from a hospital in the Peruvian jungle to a private clinic in Lima for further evaluation of two furuncular lesions not responding to antibiotics. Ten days earlier the patient noticed the appearance of two furuncular lesions on the scalp and on the right shin. The lesions were painful and associated with pruritus, no systemic symptoms were reported. He did not remember previous trauma, he also denied similar lesions on other parts of the body. No response to first generation cephalosporins and trimethoprim-sulfamethoxazole was noted.

Epidemiology: Born and lives in Lima. He works as an anthropologist mainly in contact with indigenous populations of South America. He had been working for one month in the jungle of the department of Madre de Dios in the south east region of Peru when the lesions appeared. Denies contact with known TB patients.

Physical Examination: Afebrile with normal vital signs, the patient appears in no distress. There was a tender furuncular lesion on the scalp and on the right shin, both of them showed a small break in the skin at the tip pf the lesion (Images A and B). Chest and cardiovascular examinations were normal. No organomegaly. Normal neurologic examination.

Imaging studies: Chest x-ray was normal.

Laboratory Examination: Hb: 13.0 g/dL; Hct. 40%; WBC 8 650 (neutrophils: 60%, eosinophils: 0, lymphocytes: 35%); Platelets: 246 000. Gluc: 98 mg/dL. Stool examination for ova and parasites was negative.


UPCH Case Editors: Carlos Seas, Course  Director / Paloma Carcamo, Associate Coordinator

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

 

Diagnosis: furuncular myiasis caused by Dermatobia hominis

Images for Case 2021-05
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Discussion: Surgical removal of the maggots was performed successfully, one immature larvae of the classical human botfly Dermatobia hominis was obtained from each of the two lesions (Images C and D).

Myiasis is defined as the human infestation or other vertebrates with larvae (maggots) of Diptera (or true flies), with the larvae feeding on the host´s living or necrotic tissue. Myiasis can be classified based on anatomical parameters or in ecological terms. Clinicians prefer the anatomical classification: bloodsucking, cutaneous, wound and cavitary myiasis [Clin Microbiol Revs 2012;25:79]. The families of Diptera causing various forms of myiasis are very diverse and many have specific geographic distributions.

In furuncular myiasis (cutaneous myiasis) the larva penetrates intact living skin but cannot penetrates beyond the subcutaneous tissue developing into an expanding boil-like lesion, feeding on living tissues. The full life cycle may take up to 60 days, during this time the larva maturates from as small as 6mm length to reach a maximum of approximately 2cm. When not removed before, the third stage larva comes out and pupates on soil [J Clin Aesthet Dermatol. 2013;6:47-9]. In the tropical Americas, furuncular myiasis is due to Dermatobia hominis, the human botfly. The adult female fly physically captures a mosquito and then glues her eggs to the abdomen of the carrier, when the mosquitos feeds from humans a larvae inside burrows through the skin. Botfly lesions are almost always single, and the point of the furuncle is characterized by a small punctum through which the larva must obtain oxygen [see case #6, 2005]. Discharge of an exudative material or air bubbles through the small punctum is characteristic and should raise suspicion of furuncular myiasis. Some patients mention that they feel the larva moving inside the skin, our patient did not have that feeling. Human exposure to the fly habitat as a result of tourism or business activities has increased the recognition of this infestation [Clin Microbiol Revs 2012;25:79]. Furuncular myasis accounted for 6% of all dermatological problems among returned Israeli travelers in a study; 80% of these cases acquired the infestation in South America and most of them required manual extraction only (76%). Bacterial superinfections were extremely rare (1%) [J Trav Med 2015;22:232]. The differential diagnosis of furuncular myiasis includes pyodermitis, tungiasis and insect bites. Tungiasis results from the penetration of the skin by the flea Tunga penetrans, the lesions are located usually on the feet, suspect under the presence of painful, pruriginous lesions in nail folds, toe webs, or tips of toes.

Occlusion of the respiratory punctum such as with paraffin, petroleum jelly, adhesive tape or any occlusive dressing often causes the pear-shaped larva to come out and is curative. Manual removal is indicated when the maggot does not come out after occlusion and can be performed by squeezing the larvae, use of forceps or injecting 2ml of lidocaine underneath the nodule to press the larvae to come out to the surface. [J Am Acad Dermatol. 2008;58:907-26]. This procedure is challenging as the maggot has spines in its surface that attaches to the skin and in addition, the head of it is wider and located deep in the skin tissue. Surgical excision under local anesthesia is necessary when occlusive and manual extraction fail to remove the maggot (refractory cases). A cruciate incision around the central punctum is recommended, irrigation and debridement may be needed to remove any residual tissue that may induce a severe inflammatory reaction later [J Clin Aesthet Dermatol. 2013;6:47-9].

Professor Hugo Lumbreras, the founder of our Tropical Medicine Institute, used to teach of the traditional approach to myiasis in Peru, which involved the occlusion of the entrance of the wound by a solution made from basil leaves, the odor of which forced the larvae out of the wound. The patient rejected the idea of suffocating the maggots or manually extracting them and requested a surgical extraction right away.

In Africa, furuncular myiasis is caused by Cordylobia anthropophaga or Tumbu fly (not to be confused with tungiasis). The Tumbu fly directly lays her eggs on dirty or soiled clothing. If not properly washed and ironed (heat kills the larvae) the eggs hatch and invade skin when the clothing is next worn [Am. J. Trop. Med. Hyg 2020;102: 251]. Lesions are almost always numerous and tend to be angrier and more erythematous than with the botfly. Bacterial superinfection is extremely uncommon with Cordylobia anthropophaga.

 
University of Alabama at Birmingham

Gorgas Case 2021-04

Universidad Peruana Cayetano Heredia

The following patient was seen as an outpatient at a private clinic in Lima.

Image for Case 2021-04

History: A 75-year-old male patient was transferred from a hospital in the highlands of the country to a private clinic in Lima for further evaluation of progressive swelling of the left thigh that ensued over the last 5 months. The lesion was painless, it was not associated with systemic symptoms or physical impairment, and was not related to previous trauma, he also denied similar lesions in other parts of the body or a previous febrile episode. He remembered to have had a similar but smaller lesion in the left thigh in 2016 that was treated with unknown antibiotics with full resolution.

Epidemiology: Born and lives in Huancayo, a city in the highlands of Peru. He works as a farmer and was in contact with dogs, cats, guinea pigs and pigs throughout his life. Denies any recent travel. Denies contact with TB patients.

Physical Examination: Afebrile with normal vital signs, the patient appears in no distress. There was a non-tender soft swelling of the left thigh with no inflammatory signs on the overlying skin. (Image A). Chest and cardiovascular examinations were normal. No organomegaly. Normal neurologic examination.

Imaging studies: Chest x-ray was normal. MRI of the left leg is shown in Images B and C. The abdominal ultrasound was reported as normal.

Laboratory Examination: Hb: 13.7 g/dL; Hct. 40%; WBC 7 650 (neutrophils: 60%, eosinophils: 0, lymphocytes: 35%); Platelets: 236 000. Gluc: 108 mg/dL, Creat: 0.9 mg/dL, AST 33 U/L, ALT 27 U/L, albumin 3.9 g/dL.


UPCH Case Editors: Carlos Seas, Course  Director / Paloma Carcamo, Associate Coordinator

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

 

Diagnosis: Primary skeletal muscle hydatidosis caused by Echinococcus granulosus

Images for Case 2021-04
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Discussion: The serum Western-Blot for E. granulosus infection was positive. The MRI of the left leg shows (T1 sequence with contrast) the presence of a large hydatid cyst with daughter cysts inside located in the left thigh (Images B and C). Additional images at the T1 sequence without contrast reveals that a large cyst is located in the intermediate vast of the quadriceps femoris muscle, the T2 weighted sequence revealed high signal intensity characteristic of the liquid component of the cysts (Images D,E). On further questioning, he remembered that at the age of 14 years a small cyst was identified in his right upper lung, medical treatment was offered but he does not remember further clinical or therapeutic details.

Primary skeletal muscle hydatidosis is a very rare complication of cystic hydatidosis accounting for less than 5% of all cases, and results from hematogenous dissemination of the larval stage (oncospheres). Concomitant liver and lung cysts can be observed as well. Trapping of the cysts in the capillary vessels of the liver and lungs may explain the rarity of this and other locations. The typical cystic formation may not occur in the muscles as a result of mechanical movement of the muscles and high lactic acid concentration [Can J Surg 1974;17:232]. Secondary muscle hydatidosis, or recurrent disease, results from spilling of the cystic content during a surgical procedure specially if post-surgical treatment was inadequate or not offered, or due to traumatic rupture of the cyst with subsequent spread of its content [PLoS Negl Trop Dis 5(1): e840]. The most common muscles involved are the thigh, pelvic and paravertebral muscles, including the psoas muscles [Clin Infect Dis 2001;32:e65]. The clinical presentation is related to the dimensions of the cyst, and includes pain, deformity of the area involved, limitations to perform physical activity, vascular insufficiency due to compression and complications such as anaphylactic reactions due to the partial or total rupture and superinfections. In rare cases, bone involvement may occur with osteolytic lesions mimicking neoplastic or bacterial involvement. Diagnosis may be difficult as the clinical picture and the images mimic other conditions such as cancer or pyogenic infections. Serology may be negative as well. High index of suspicion and proper reading of images including ultrasound, CT Scan or MRI are very useful. Ultrasound is the imaging of first choice, when non diagnostic, a CT-Scan may help showing daughter cysts and increased density of the hydatid membrane [Parasitol Int 2008;57:8]. Findings at the MRI include at T1 diverse patterns of signal intensity and at T2 the liquid content of the cyst is revealed, but these findings are non-specific [Clin Infect Dis 2001;32:e65; Int J Sur Case Reports 2018;51:379].

Human hydatid disease secondary to Echinococcus granulosus is caused by the larval form of this dog tapeworm. Humans ingest the tapeworm eggs in environments contaminated by canine feces and become accidental intermediate hosts. This patient had ongoing exposure to dogs during his entire life. Sheep are the normal intermediate hosts. In general, disease is diagnosed in adulthood as larval cysts expand slowly over years or decades, becoming symptomatic as they impinge on other structures by virtue of their size. The cysts contain hundreds of viable protoscoleces capable of becoming adult tapeworms upon ingestion by a definitive host such as the dog. The internal germinal membrane lining the cyst produces new protoscoleces on an ongoing basis and may also produce internal daughter cysts. Each protoscolex is capable of becoming a new cyst should the original cyst rupture or be ruptured. Cystic hydatid disease due to E. granulosus is common in sheep and cattle raising areas worldwide. Most primary infections involve a single cyst. In adults, 65% of solitary cysts are found in liver, 25% in lung and the rest in a wide variety of other organs including kidney, spleen (see case #7, 2009), heart, bone, muscles and brain (see case #5-2014). This is the first case of a well-documented skeletal muscle hydatidosis presented as a case of the week since we started posting cases in 2001.

Differential diagnosis of swelling of the thighs includes malignancy, hematoma, osteomyelitis and pyogenic myositis. Diagnosing malignancies requires a tissue sample. Pyogenic myositis in the tropics is more commonly seen in children (tropical pyomyositis, see case #9-2002), aspiration of the abscess reveals purulent material, Staphylococcus aureus is the most common pathogen involved (95% in the tropics), patients are usually febrile and with marked tenderness. Chronic osteomyelitis with swelling of soft tissues and drainage of purulent material through sinus tracts is easily recognized in a plain x-ray film.

The treatment of choice for skeletal muscle hydatidosis is surgical removal of the cyst. The WHO recommends pre- and post-surgical treatment with albendazole. Duration of pre-surgical treatment is not well defined, courses as long as 3 months resulted in 94% elimination of viable cysts [PLoS Negl Trop Dis 5(1): e840]. Post-surgical treatment for one month with albendazoles is recommended by WHO. For patients in whom the surgical resection is not possible, or in those with recurrent disease after surgery the PAIR procedure (puncture, aspiration, injection and re-aspiration) plus antiparasitic treatment may be an option, but there is no experience with this procedure in muscle hydatidosis [PLoS Negl Trop Dis 5(1): e840]. Our patient was scheduled for surgical resection after receiving a course of albendazole plus praziquantel for one month but he acquired COVID-19 and was lost to follow-up.

 
University of Alabama at Birmingham

Gorgas Case 2021-03

Universidad Peruana Cayetano Heredia

The following patient was seen as an outpatient at the dermatology clinic at Hospital Cayetano Heredia. We would like to thank Dr. Ramos and Dr. Bravo for their assistance with this case.

Image for Case 2021-03

History: A 55-year-old man presents with a history of illness of approximately 40 years, which started with a non-painful, non-pruritic, small elevated erythematous lesion over his left knee which slowly grew over the decades. He treated it with topical antibiotics and corticosteroids on several occasions, with no improvement. He denies any other symptoms including neuropathy. He has had no other skin problems in the past 40 years that he can recall.

Epidemiology: Born in Chiclayo, a city on the northern coast of Peru. He moved to Lima approximately 30 years ago and works as an electrician. Denies any recent travel. Denies past medical or surgical history, does not recall if he received BCG vaccine. Denies contact with TB patients. No notable family history of infections or immunodeficiencies.

Physical Examination: Examination of the skin revealed an erythematous, serpiginous, verrucous plaque in the extensor surface of the knee which extended to the sides, with central atrophy, some hyperalgesia and preserved sensation (Images A and B). Joint mobility was unaffected. No lymphadenopathy. The rest of the exam was unremarkable.

Imaging studies: CXR was normal (Image C).

Laboratory Examination: Hb: 14.7 g/dL; Hct. 44%; WBC 4 550 (neutrophils: 62%, eosinophils: 1, lymphocytes: 30%); Platelets: 200 000. Gluc: 98 mg/dL, Urea: 17 mg/dL, Creat: 1.0 mg/dL, AST 22 U/L, ALT 17 U/L, GGT 31 U/L, albumin 4.2 g/dL.


UPCH Case Editors: Carlos Seas, Course  Director / Paloma Carcamo, Associate Coordinator

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

 

Diagnosis: Cutaneous tuberculosis due to Mycobacterium tuberculosis - Lupus vulgaris form

Images for Case 2021-03
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Discussion: Tuberculin skin testing (TST) was positive (15mm), and a skin biopsy revealed tuberculoid granulomas, with giant multinucleated cells and central caseation (Image D). These findings and the clinical presentation of the patient are sufficient to make a diagnosis of lupus vulgaris. Acid-fast stain of the sputum was negative for mycobacteria. Cultures are pending.

Cutaneous tuberculosis accounts for 1-1.5% of diagnosed extrapulmonary tuberculosis cases, which comprise only 8.4-13.7% of all tuberculosis cases (https://www.ncbi.nlm.nih.gov/pubmed/26616847). The clinical presentation depends on the path of bacterial entry into the skin, the immune status of the host, and whether the host was previously exposed and/or sensitized to Mycobacterium tuberculosis (MTB). An observational study conducted in the northern coast of Peru showed that lupus vulgaris was the second most common form of cutaneous tuberculosis in the region, after scrofuloderma. Erythema induratum and erythema nodosum were the least frequently diagnosed forms (https://pesquisa.bvsalud.org/portal/resource/es/lil-483653).

Cutaneous tuberculosis may also be classified depending on the number of mycobacteria that can be identified from the lesions. Paucibacillary forms include tuberculosis verrucosa cutis and lupus vulgaris. Multibacillary forms include primary inoculation tuberculosis, scrofuloderma, tuberculosis cutis orificialis, acute miliary tuberculosis, and tuberculous gumma.

Lupus vulgaris is typically seen in patients with prior exposure to MTB complex, with a moderate or high immune response to it. Along with scrofuloderma, it is the most commonly reported cutaneous manifestation of tuberculosis (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302357/). In lupus vulgaris, the infection may occur through direct inoculation, via hematogenous or lymphatic spread, through extension from a deeper focus or, rarely, after BCG vaccination. Lesions start as small red-brown papules, known as “lupornes”, which coalesce and form a plaque that grows slowly, without any other symptoms. In time, the edges of the plaque may become verrucous and serpiginous, and the center may clear, showing signs of atrophy. The classical plaque has a soft, gelatinous consistency, described as apple-jelly nodules on diascopy (https://www.ncbi.nlm.nih.gov/pubmed?term=17350496). Other presentations include hypertrophic, ulcerative, and vegetative lesions. When lesions are located on the face deeper involvement may occur affecting the nose, lips and ears. If there is immunosuppression, patients may develop multiple lesions (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2923933/). If left untreated, lesions will continue to grow indefinitely, and may become malignant (https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1529-8019.2008.00186.x).

The differential diagnosis for lupus vulgaris includes deep fungal infections (chromoblastomycosis, lobomycosis), non-venereal trepanomatosis, leishmaniasis, late syphilis, and tuberculoid leprosy. Chromoblastomycosis also presents with long-term evolution as in this case (see case of the week #3, 2014), classical features such as presence of dark dots in the lesion are absent in this case. Lobomycosis may also present with very chronic evolution, absence of typical yeast cells forming chains in the skin biopsy with HE stain is against this condition (see case of the week #3, 2005). Cutaneous leishmaniasis rarely presents with this chronic evolution. Tertiary syphilis may present with chronic skin involvement, but the pathological and clinical features of this case are not consistent with syphilis. The non-venereal trepanomatosis (yaws, pinta and begel) are conditions to consider in this case. These entities present in three clinical stages including early and late stages. Yaws (T. pallidum pertenue) affects mostly children, usually starting with a single lesion but secondary lesions subsequently appear that typically ulcerate, in late stages bone involvement occurs. Asymptomatic periods are followed by development of new lesions. Pinta (T. pallidum carateum) is more common in adults and does not affect deep tissues as yaws does. Hypopigmentation and scarring of the skin are common clinical features in this condition. Pinta has rarely been reported in Peru and no reports of yaws exist. Begel (T. pallidum endemicum) is another non-venereal trepanomatosis that mostly affects children; it has not been reported in Peru and affects predominantly the oral mucosa.

Diagnosis is a challenge, as lupus vulgaris is paucibacillary and demonstration of acid-fast bacilli is often not possible. Histopathology of a skin biopsy reveals tuberculoid granulomas with or without caseation, with few or no bacilli. Mycobacterial cultures are usually negative, however, TSTs are usually positive. PCR for mycobacteria is accurate and rapid, and even allows for differentiation of MTB from other non-tuberculous mycobacteria if the right primers are chosen, but requires high-complexity laboratories and skilled technicians (https://onlinelibrary.wiley.com/doi/abs/10.1046/j.1365-4362.2003.01461.x).

Management is no different than that for pulmonary tuberculosis. Patients should be started on standard multidrug treatment. Since it is difficult to culture mycobacteria for this form of tuberculosis, it may not be possible to establish sensitivities. The choice of a regimen should then consider patients’ immune status and comorbidities, and local resistance patterns. Patients typically show clinical improvement after 6 weeks of treatment (https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1529-8019.2008.00186.x). Surgical removal of lesions may be used as adjuvant therapy, especially in localized lesions (https://www.asmscience.org/content/journal/microbiolspec/10.1128/microbiolspec.TNMI7-0010-2016). Our patient is currently in his fourth week of treatment with HRZE, with slight improvement in lesions. The extension of the cutaneous involvement precludes surgical excision which is recommended for smaller lesions.

 
University of Alabama at Birmingham

Gorgas Case 2021-02

Universidad Peruana Cayetano Heredia

The following patient was hospitalized in the Tropical Medicine ward of Cayetano Heredia Hospital on February 24th, 2021.

Image for Case 2021-01

History: A 34-year-old male patient presented with a 1-month history of intermittent intense holocranial headaches accompanied by nausea and occasional vomiting, followed one week later by fever to 38°C; both were relieved by acetaminophen. Two weeks prior to admission, he noticed the new appearance of a non-pruritic rash on his thorax, arms, and face. On the day of presentation to Cayetano Heredia Hospital, the nausea and vomiting had worsened, he had generalized weakness, asthenia, and diaphoresis.

Epidemiology: Born and lives in Lima. Works in an electronics store. Multiple unprotected sexual encounters in the last months. No history of TB exposure. No previous STI or HIV tests.

Past Medical History: Hospitalized for COVID-19 six months prior to admission.

Physical Examination: BP:120/84, HR 120, RR 24, T 38°C. SatO2: 98% (FiO2 0.21). Skin examination revealed multiple skin-colored umbilicated papules, some with central necrosis, in varying sizes and painless, in face, thorax, genitalia and upper and lower extremities (Image A). Oral examination revealed white lesions in the buccal mucosa and soft palate. Chest and abdominal examinations were unremarkable. Neurological examination revealed nuchal rigidity. Fundoscopy was not performed.

Imaging studies: Chest X-ray is shown in Image B. CT Scan of the brain was not performed.

Laboratory: Hb: 13.3 g/dL; Hct. 40%; WBC 5 440 (neutrophils: 79%, eosinophils: 0.2%, lymphocytes: 16%); Platelets: 216 000. INR 1.21, PT 16.4, PTT 43.4. Gluc: 102 mg/dL, Urea: 34 mg/dL, Creat: 0.8 mg/dL, AST 39, ALT 21, GGT 51, Alk Phos 104, LDH 403, albumin 3.6. Serology for HIV 1-2 positive. Serology for HTLV-1 negative. AntiHBc, HBsAg, antiHbs non-reactive. RPR non-reactive. CD4 cell count and viral load determinations are pending.

CSF: Xanthochromic, glucose 28, protein 32, no WBC, 300 RBC/mm3, ADA 6.15, opening pressure: 30 cmH2O


UPCH Case Editors: Carlos Seas, Course  Director / Paloma Carcamo, Associate Coordinator

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

 

Diagnosis: Disseminated cryptococcosis in a recently diagnosed HIV patient

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Discussion: A KOH stain of the patient’s CSF revealed multiple budding yeasts, and the diagnosis of cryptococcal meningitis was then confirmed by India Ink examination (Image C). Microscopy of a biopsy of a skin lesion also revealed typical Cryptococcus sp. yeasts (Image D). Latex agglutination test was unavailable. Cultures are underway.

Cryptococcal meningitis (CM) is the one of the most common causes of diffuse central nervous system involvement in HIV-infected patients. In our institution, CM is the second leading cause of admission in our institution, after tuberculosis; 234 patients with CM and HIV were discharged over a period of 13 years, 77% were males, mean age was 35 years, 24% had a previous episode of CM; median CD4 count was 33 cells/mm3, and only 17% were receiving ART (1).  Disseminated cryptococcosis is defined by isolation of microorganisms from at least two different sites, or a positive lung culture. Skin lesions are typically associated with CNS disease and usually represent hematogenous spread. They may have different morphologies, including pustules, papules, ulcers, cellulitis, plaques, abscesses, or, as was seen in the presented case, umbilicated papules (Image A). The differential diagnosis for umbilicated papules in an immunocompromised patient also includes molluscum contagiosum, and other fungal infections such as histoplasmosis, paracoccidioidomycosis or, in the right geographical setting, talaromycosis.

Diagnosis of CM relies on the isolation of Cryptococcus from suitable samples or antigenic testing. However, certain clinical features may make the diagnosis more likely. An opening CSF pressure of 25 cmH2O or more is found in more than half of patients with cryptococcal meningitis (2). This, in conjunction with the characteristic low CSF cell count, helps differentiate cryptococcal meningitis from other causes of CNS involvement such as syphilis, tuberculosis, or listeria. WHO recommends the use of a rapid diagnostic antigenic test, either a lateral flow assay or a latex agglutination test. If these tests are not available, then an India ink stain is recommended (3). While lumbar punctures (LP) are diagnostic and permit measuring the opening pressure, they may be contraindicated in cases of significant coagulopathy, suspected space-occupying lesion, or major spinal deformity. In resource limited settings where neuroimaging may not be available, the risk-benefit analysis favors performing an LP unless a clear contraindication exists, such as focal neurological signs or recurrent seizures (3). If an LP cannot be performed, then serum antigenic tests are recommended. If the results are negative, another diagnosis should be considered. Follow-up cultures are not indicated unless the patient is not responding to medical treatment. Serologic or CSF antigenic tests are not recommended to follow-up response to treatment.

The cornerstones of the treatment of cryptococcal meningitis in an immunocompromised patient are antifungal therapy, control of intracranial pressure, and immune recovery.

Antifungal therapy should consist of an induction phase lasting two weeks, then consolidation therapy for eight weeks, and finally suppressive therapy for at least one year. WHO recommends first-line induction therapy with both amphotericin B and flucytosine for one week followed by one week of fluconazole (3). If flucytosine is unavailable, fluconazole may be used, though it does not have the same early fungicidal activity as the combination with flucytosine (4). A study to determine predictors for negative cultures at two weeks (early fungicidal activity) of induction therapy was conducted in our hospital (1).Two variables at baseline were associated with not achieving early fungicidal activity: high opening pressure (>35 cmH2o) and high fungal burden (4.5 log10 CFU/ml). After induction, patients should receive fluconazole for consolidation, and then a lower dose for suppression.

Increased intracranial pressure should be managed aggressively with therapeutic lumbar punctures to achieve an opening pressure of less than 20cm H2O, or with drains. Diuretics and corticosteroids should not be used. The inpatient mortality in our hospital is 20%; 35% of these patients died in the first two weeks of treatment (1).

Antiretroviral therapy should be started 2-10 weeks after starting antifungal therapy, to reduce the risk of IRIS.

Our patient is currently receiving induction therapy with amphotericin B and fluconazole, with regular therapeutic lumbar punctures.

References:

1. Concha-Velasco F, González-Lagos E, Seas C, Bustamante B. Factors associated with early mycological clearance in HIV-associated cryptococcal meningitis. PLOS ONE. 2017 Mar 29;12(3):e0174459.

2. Graybill JR, Sobel J, Saag M, van der Horst C, Powderly W, Cloud G, et al. Diagnosis and Management of Increased Intracranial Pressure in Patients with AIDS and Cryptococcal Meningitis. Clinical Infectious Diseases. 2000 Jan 1;30(1):47–54.

3. Guidelines for The Diagnosis, Prevention and Management of Cryptococcal Disease in HIV-Infected Adults, Adolescents and Children: Supplement to the 2016 Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection [Internet]. Geneva: World Health Organization; 2018 [cited 2021 Mar 12]. (WHO Guidelines Approved by the Guidelines Review Committee). Available from: http://www.ncbi.nlm.nih.gov/books/NBK531449/

4. Day JN, Chau TTH, Wolbers M, Mai PP, Dung NT, Mai NH, et al. Combination antifungal therapy for cryptococcal meningitis. N Engl J Med. 2013 Apr 4;368(14):1291–302.

 
University of Alabama at Birmingham

Gorgas Case 2021-01

Universidad Peruana Cayetano Heredia

The Gorgas Courses in Clinical Tropical Medicine are usually given at the Tropical Medicine Institute at Cayetano Heredia University in Lima, Peru. This year, due to the pandemic, we have started the 26th edition of the Gorgas Course in Clinical Tropical Medicine in a mixed educational model involving a virtual format, which will be followed by a live session at the Tropical Medicine Institute. New cases will be published every two weeks for the next seventeen weeks. Each case includes a brief history and digital images pertinent to the case. A link to the actual diagnosis and a brief discussion follows.

Carlos Seas and German Henostroza
Course Directors.

The following patient was hospitalized on the Internal Medicine ward of Cayetano Heredia Hospital on December 1st, 2020.

Image for Case 2021-01

History: A 51-year-old female patient presented with a 6-month history of non-productive cough. Two weeks prior to admission the patient noted worsening of her cough, as well as subjective fevers, shortness of breath on exertion, and back pain. The patient continued to deteriorate to the point of having shortness of breath on rest for which she decided to go to the Emergency Department at Cayetano Heredia Hospital for further evaluation.

Epidemiology: Born in Iquitos, a city in the Amazon jungle; has lived in Lima for the past 2 years. Works as a homemaker. Her father had tuberculosis 10 years ago.

Physical Examination: BP:90/60, HR 92, RR 32, T 38.9°C. SatO2: 89% (FiO2 100% - reservoir mask). Skin and mucosae were pale. Patient was tachypneic; lung examination revealed chest retractions, diminished breath sounds in both bases and diffuse crackles. Cardiac and abdominal examinations were unremarkable. The patient was alert, oriented, without significant neurological deficits.

Imaging Studies: Chest x-ray showed bilateral alveolar infiltrates, air bronchograms, and a lesion in upper left lobe (Image A). Chest CT showed bilateral diffuse alveolar infiltrates, with air bronchograms (Image B).

Laboratory: Hb: 11.2 g/dL; Hct. 33%; WBC 11 880 (neutrophils: 93%, eosinophils: 0.1%, lymphocytes: 0.4%); Platelets: 284 000. ABG: pH 7.2, PO2 81.7, PCO2 65.4, Pa/Fi 148, HCO3 25.9, Lactate 1.8. INR 1.19, PT 15.6, PTT 49.5. Gluc: 115 mg/dL, Urea: 74 mg/dL, Creat: 1.6 mg/dL, AST 85, ALT N/A, GGT 169, Alk Phos 281, LDH 565, albumin 1.8. HIV, HBsAg, HTLV-1/2 were non-reactive. VDRL negative. Antibody test for COVID-19 was IgG positive but PCR was unavailable. A sputum sample was sent to the laboratory.


UPCH Case Editors: Carlos Seas, Course  Director / Paloma Carcamo, Associate Coordinator

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

 

Diagnosis: Bilateral pulmonary tuberculosis and Strongyloides hyperinfection.

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Discussion: Shortly after admission, the patient deteriorated and required intubation and mechanical ventilation. She was started on empiric treatment with dexamethasone for severe COVID-19. AFB in sputum was positive 2+, and GeneXpert MTB/RIF detected M. tuberculosis without rifampicin resistance. Two weeks after admission, because she was not improving after initiation of 4-drug TB therapy, a bronchial aspirate was sent to the lab, and filariform larvae of Strongyloides sp. were found (Image C), and a diagnosis of Strongyloides hyperinfection was made.

Not all patients presenting with respiratory distress amid the pandemic will have COVID-19 and it cannot be ruled in or out using a rapid antibody test. Rapid antibody tests should not be used for diagnostic purposes, as they are not useful to differentiate acute disease from past infection, or even from infection with other coronaviruses. In the presented case, it is likely that the patient had positive IgG due to a past infection.

Bilateral involvement is an unusual presentation of pulmonary tuberculosis in immunocompetent individuals. One observational study found that around 35% of patients with pulmonary tuberculosis had bilateral infiltrates (1)." All investigations for risk factors for immunosuppression (HIV, HTLV, neoplasms) besides use of corticosteroids have so far been negative for the present patient.

Strongyloidiasis, on the other hand, is an endemic infection caused by the nematode Strongyloides stercoralis in tropical and subtropical regions. It is hard to estimate its prevalence because the larvae are not easily seen by direct stool examination without concentration techniques; however, some studies estimate a worldwide prevalence of about 8.1% (2). A study conducted in a rural community in the Peruvian Amazon found that 8.7% of the analyzed stool samples had S. stercoralis larvae, and 72% of the analyzed serum samples had a positive ELISA (3).

S. stercoralis has both free-living and parasitic stages. Adult female worms live in the human small intestine, laying eggs that hatch into rhabditiform larvae, which are shed in the stool. They then grow into either infective filariform larvae or free-living adults. Filariform larvae can infect humans transcutaneously. They enter the bloodstream, are carried to the lungs and are then swallowed to enter the digestive tract. However, some rhabditiform larvae may mature into filariform larvae prior to being shed and may re-infect the host by invading either the intestinal wall or the perineum. This is denominated an autoinfective cycle.

The use of corticosteroids at any dose is a well-known risk factor for Strongyloides hyperinfection, though the dose and duration of treatment that confer increased risk are unclear. A study in Thailand suggested that there was more risk with a duration of therapy of less than 50 days, with a median daily prednisolone-equivalent dosage of 40mg, which would be equivalent to 6mg dexamethasone (the recommended daily dose for severe COVID-19) (4). This effect might be mediated by inhibition of eosinophil and lymphocyte activation, or by increasing the fertility of adult female worms. Hyperinfection may occur as early as 20 days after starting corticosteroid therapy, or as late as years later (5). Cases of Strongyloides hyperinfection secondary to corticosteroids given for COVID-19 have been reported in the literature (6,7). Given that fatality rates for this syndrome can be as high as 70-100%, patients at risk of exposure to Strongyloides should be screened or pre-emptively treated with ivermectin (8). Most disseminated or hyperinfected Strongyloides cases in our institution are HTLV-1 associated. This patient deviates from this pattern, and we are still looking for more evidence of immune suppression.

The patient was started on oral ivermectin and standard treatment for tuberculosis. She improved and is now being weaned off a tracheostomy.

References:

1.  Rai, Deependra K et al. “Radiological difference between new sputum-positive and sputum-negative pulmonary tuberculosis.” Journal of family medicine and primary care vol. 8,9 2810-2813. 30 Sep. 2019

2. Buonfrate D, Bisanzio D, Giorli G, Odermatt P, Fürst T, Greenaway C, et al. The Global Prevalence of Strongyloides stercoralis Infection. Pathogens. 2020 Jun;9(6):468.

3. Yori PP, Kosek M, Gilman RH, Cordova J, Bern C, CHAVEZ CB, et al. Seroepidemiology of Strongyloidiasis in the Peruvian Amazon. Am J Trop Med Hyg. 2006 Jan;74(1):97–102.

4. Asdamongkol N, Pornsuriyasak P, Sungkanuparph S. Risk factors for strongyloidiasis hyperinfection and clinical outcomes. Southeast Asian J Trop Med Public Health. 2006 Sep;37(5):875–84.

5. Al Maslamani MA, Al Soub HA, Al Khal ALM, Al Bozom IA, Abu Khattab MJ, Chacko KC. Strongyloides stercoralis hyperinfection after corticosteroid therapy: a report of two cases. Ann Saudi Med. 2009;29(5):397–401.

6. Lier AJ, Tuan JJ, Davis MW, Paulson N, McManus D, Campbell S, et al. Case Report: Disseminated Strongyloidiasis in a Patient with COVID-19. The American Journal of Tropical Medicine and Hygiene. 2020 Aug 14;103(4):1590–2.

7. Marchese V, Crosato V, Gulletta M, Castelnuovo F, Cristini G, Matteelli A, et al. Strongyloides infection manifested during immunosuppressive therapy for SARS-CoV-2 pneumonia. Infection. 2020 Sep 10;1–4.

8. Requena-Méndez A, Buonfrate D, Gomez-Junyent J, Zammarchi L, Bisoffi Z, Muñoz J. Evidence-Based Guidelines for Screening and Management of Strongyloidiasis in Non-Endemic Countries. Am J Trop Med Hyg. 2017 Sep;97(3):645–52.