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Case of the Month 

September 2021

Lyle Murray, MBChB, FCP (SA), MMed, DPhil

Jarrod Zamparini, MBChB, FCP (SA), MMed

Sarah Stacey, MBBCh, FCP (SA), Cert ID (SA), DTM&H

Jeremy Nel, MBChB, FCP (SA), Cert ID (SA), MMed, DTM&H 

Division of Infectious Diseases, Department of Internal Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa

 

Case presentation 

A 36-year-old HIV-infected male presented to a Johannesburg hospital at the end of April 2021 complaining of worsening dyspnoea, chronic productive cough, fatigue, and nightsweats. He also had an eight-week history of skin rash on his face, neck, trunk, and limbs. He had been diagnosed with HIV two months prior to this presentation and initiated on a fixed-dose combination of tenofovir, lamivudine and dolutegravir and isoniazid prophylaxis at that time. 

The skin lesions were not painful, were non-pruritic and were noted to have started prior to the initiation of the antiretrovirals and isoniazid. He had no history of prior chronic illness including tuberculosis. 

On examination the patient appeared chronically ill with generalised wasting and shotty generalised, lymphadenopathy. His blood pressure was 118/76 mmHg, pulse 114 bpm, temperature of 37.8 °C and respiratory rate of 24 bpm. 

A dermatological examination revealed diffuse, erythematous, scaly papules with nodules and plaques over the face, neck, trunk and limbs (Figures 1 A-D). Some lesions were confluent. There was no mucous membrane involvement, and his hair was noted to be frail with diffuse alopecia. On auscultation of his chest he had bilateral crackles and his cardiovascular, abdominal and neurological examinations were unremarkable.

Images

Infectious differential diagnosis for the cutaneous manifestations

 

1.     Disseminated mycosis

Disseminated mycoses in immunocompromised individuals frequently present with cutaneous manifestations as part of multisystem involvement1. In the South African context, particular mycoses to consider would include histoplasmosis, emergomycosis, cryptococcosis, sporotrichosis and blastomycosis. The morphology of cutaneous lesions is varied in mycoses and includes papules, nodules, ulcers, plaques and erythema2. Sporotrichosis typically presents with lymphocutaneous spread and cryptococcosis as skin-coloured papules or nodules. In this case the cutaneous manifestations are most suggestive of emergomycosis and histoplasmosis.

 

2.     Disseminated tuberculosis with skin involvement

Cutaneous involvement is a rare manifestation of extrapulmonary tuberculosis and may include papules, warty lesions, ulcers and plaques3.The extensive nature of the skin involvement in this case would indicate either haematogenous spread in the form of acute miliary tuberculosis or papulonecrotic tuberculid. Papulonecrotic tuberculid, although fitting morphologically in this case, is very unlikely in a patient with such severe immune suppression. The chest x-ray features are also not suggestive of miliary tuberculosis. A skin biopsy would be necessary to diagnose both of these conditions.

3.     Pruritic papular eruption (PPE) of HIV

PPE is the most common rash associated with HIV infection and increases in frequency in individuals with advanced immunosuppression, such as in this case4. Lesions are commonly papular, may progress to become macular and nodular and are generally more confined to the extremities5. The lack of pruritis in this case combined with the extensive distribution of the lesions argues strongly against a diagnosis of PPE.

4.     Syphilis

The rash of secondary syphilis can present in varied forms but is most commonly diffuse and symmetrical, involving macular or papular lesions on the trunk and extremities and frequently involves the palms and soles6. The rash is typically non-pruritic, and alopecia is common. A combination of treponemal and non-treponemal tests are required for the diagnosis. 

 

Final diagnosis 

1.     Pulmonary tuberculosis (Rifampicin-sensitive)

2.     Disseminated emergomycosis/histoplasmosis

Discussion 

The fungus Emergomyces africanus was first described as a cause of disseminated disease in individuals with advanced HIV in 2013 and has since been shown to be the most common systemic dimorphic mycosis in this patient population in South Africa2,7. Histoplasmosis is predominantly caused by Histoplasma capsulatum var. capsulatum in southern Africa, whilst Histoplasma capsulatum var. duboisii is more frequent in central and western Africa8. The route of infection for both emergomycosis and histoplasmosis is via inhalation of aerosolised microconidia released from soil. In the warmer environment of the lung, the conidia transform into oval yeasts, replicate and disseminate via the lymphatics and blood1

In advanced HIV, histoplasmosis and emergomycosis should form part of any differential diagnosis for widespread skin lesions. In addition to cutaneous involvement, disseminated disease may involve the pulmonary, gastrointestinal, haematological, neurological and urogenital systems1

Diagnosing emergomycosis/histoplasmosis 

The diagnosis of emergomycosis and histoplasmosis can be challenging and is complicated by the fact that, within the context of advanced HIV, the two diseases are clinically indistinguishable9.  

Relevant clinical specimens may include blood and bone marrow aspirates for fungal culture, sputum and bronchoalveolar lavage fluid for microscopy and fungal culture and urine for histoplasma antigen detection. Tissue from skin biopsy, lymph node biopsy or bone marrow trephine should be sent for histopathology, fungal culture and PCR studies, if available. Microscopy and histopathology using calcofluor white, PAS and methenamine silver stains are useful to identify fungal elements but may not sufficiently identify the specific causal pathogen9. Fungal culture with ancillary PCR and sequencing of the internal transcribed spacer (ITS) region of ribosomal DNA is considered as the gold standard for identification but has limited availability in resource-poor settings1.  

The similarities and differences in the use of diagnostic modalities for emergomycosis and histoplasmosis are summarised in the table below. 

Differentiating emergomycosis and histoplasmosis

Recommended reading

 

Samaddar, A. & Sharma, A. Emergomycosis, an Emerging Systemic Mycosis in Immunocompromised Patients: Current Trends and Future Prospects. Front. Med. 0, 550 (2021).

 

Schwartz, I. S. et al. AIDS-Related Endemic Mycoses in Western Cape, South Africa, and Clinical Mimics: A Cross-Sectional Study of Adults with Advanced HIV and Recent-Onset, Widespread Skin Lesions. Open Forum Infect. Dis. 4, 1–7 (2017).

 

Govender, N. P. & Grayson, W. Emergomycosis (Emergomyces africanus) in Advanced HIV

Disease. Dermatopathology 6, 63–69 (2019).

 

Oladele, R. O., Ayanlowo, O. O., Richardson, M. D. & Denning, D. W. Histoplasmosis in

Africa: An emerging or a neglected disease? PLoS Negl. Trop. Dis. 12, (2018).

 

PAHO and WHO. Guidelines for Diagnosing and Managing Disseminated Histoplasmosis among People Living with HIV. Guidelines for Diagnosing and Managing Disseminated Histoplasmosis among People Living with HIV (2020)

References  

  1. Samaddar, A. & Sharma, A. Emergomycosis, an Emerging Systemic Mycosis in Immunocompromised Patients: Current Trends and Future Prospects. Front. Med. 0, 550 (2021).
  2. Schwartz, I. S. et al. AIDS-Related Endemic Mycoses in Western Cape, South Africa, and Clinical Mimics: A Cross-Sectional Study of Adults with Advanced HIV and Recent-Onset, Widespread Skin Lesions. Open Forum Infect. Dis. 4, 1–7 (2017).
  3. Van Zyl, L., Du Plessis, J. & Viljoen, J. Cutaneous tuberculosis overview and current treatment regimens. Tuberculosis 95, 629–638 (2015).
  4. Claasens, S. et al. The prevalence and spectrum of mucocutaneous disease in South African people living with HIV and accessing care at a district-level hospital. South. Afr. J. HIV Med. 21, (2020).
  5. Chelidze, K., Thomas, C., Chang, A. Y. & Freeman, E. E. HIV-Related Skin Disease in the Era of Antiretroviral Therapy: Recognition and Management. Am. J. Clin. Dermatol. 20, 423–442 (2019).
  6. Lautenschlager, S. Cutaneous manifestations of syphilis: Recognition and management. American Journal of Clinical Dermatology 7, 291–304 (2006).
  7. Kenyon, C. et al. A Dimorphic Fungus Causing Disseminated Infection in South Africa. N. Engl. J. Med. 369, 1416–1424 (2013).
  8. Oladele, R. O., Ayanlowo, O. O., Richardson, M. D. & Denning, D. W. Histoplasmosis in Africa: An emerging or a neglected disease? PLoS Negl. Trop. Dis. 12, (2018).
  9.  Govender, N. P. & Grayson, W. Emergomycosis (Emergomyces africanus) in Advanced HIV Disease. Dermatopathology 6, 63–69 (2019).
  10. Schwartz, I. S. et al. Emergomyces: The global rise of new dimorphic fungal pathogens. PLoS Pathog. 15, 1–7 (2019).
  11. 11.     Azar, M. M. & Hage, C. A. Laboratory diagnostics for histoplasmosis. J. Clin. Microbiol. 55, 1612–1620 (2017).
  12. Maphanga, T. G. et al. Cross-reactivity of a Histoplasma capsulatum antigen enzyme immunoassay in urine specimens from persons with emergomycosis in South Africa. Med. Mycol. 59, 672–682 (2021).
  13. Schwartz, I. S. et al. Clinical Characteristics, Diagnosis, Management, and Outcomes of Disseminated Emmonsiosis: A Retrospective Case Series. Clin. Infect. Dis. 61, 1004–1012 (2015).
  14. Maphanga, T. G. et al. In vitro antifungal susceptibility of yeast and mold phases of isolates of dimorphic fungal pathogen Emergomyces africanus (formerly Emmonsia sp.) from HIV-infected South African patients. J. Clin. Microbiol. 55, 1812–1820 (2017).
  15. PAHO and WHO. Guidelines for Diagnosing and Managing Disseminated Histoplasmosis among People Living with HIV. Guidelines for Diagnosing and Managing Disseminated Histoplasmosis among People Living with HIV (2020). doi:10.37774/9789275122488
  16. Schwartz, I. S. & Wasserman, S. Itraconazole and antiretroviral therapy: strategies for empirical dosing. Lancet Infect. Dis. 17, 1122–1123 (2017).

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