Gorgas Case of the Week - 2021 Series

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

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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.