William Worodria Mulago Hospital, Kampala, Uganda The AIDS patient with a ‘respiratory’ presentation – diagnostic considerations William Worodria Mulago Hospital, Kampala, Uganda

Outline The burden of Respiratory Illness The Diagnostic Approach to a patient with a “respiratory” presentation Community Acquired Pneumonia Tuberculosis Pulmonary Kaposi Sarcoma Fungal infections Others

Burden of Respiratory Illness in the AIDS patient Pulmonary complications are the commonest presentation in AIDS patients Present as a variety of infectious and non infectious diseases Community acquired pneumonia (CAP) is the commonest cause of respiratory disease The high risk of CAP persists despite the use of Highly Active Antiretroviral therapy Recurrent CAP is an AIDS-defining condition

Important considerations To obtaining the ideal sample for diagnosis To use a test with the most suitable performance characteristics

Samples for diagnosis of respiratory disease Sputum – spontaneously expectorated or induced Serum Body fluids – pleural, gastric, etc Bronchoalveolar lavage Biopsy or aspirate

Community Acquired Pneumonia

Major cause of morbidity and mortality in HIV X 6 incidence in HIV+ vs HIV- Mortality x 4 in subjects with pneumonia vs without Commonest pathogens S. pneumonia S. aureus H. Influenza K. pneumonia (NEJM, 2005)

Diagnostic Considerations for CAP Symptoms including cough, chest pain, difficulty in breathing and fever of recent onset Chest radiograph Sputum Gram stain & culture Other tests (not routine): Blood cultures Urinary Binax Legionella Urinary Antigen Pneumococcal PCR Acute and convalescent sera for Chlamydophila pneumoniae and Mycoplasma pneumoniae

Diagnosis of Community Acquired Pneumonia The clinical signs and radiological features may be similar in HIV+ and HIV-ve persons The management of CAP is compromised by the lack of bacteriological confirmation (Pefura Yone, BMC Pulm Med 2012, 12(46)) Treatment is mostly empirical, based on known local epidemiological patterns Non response to treatment for CAP prompts further evaluation for other pathogens

Pathogens were identified in 853 (38%) 2488 adults with radiographic evidence of pneumonia enrolled from five hospitals Cultures, serological testing, antigen detection, molecular diagnostics Pathogens were identified in 853 (38%) (NEJM 2015; 373: 415-27)

Tuberculosis

Tuberculosis A leading cause of death from a single infectious agent 10.4 million people had TB disease in 2016 and 1,674,000 died from TB disease. 87% patients with TB occurred in Africa, Asia and the Western Pacific region. (Global TB Report, 2017) Advanced HIV-related immune suppression may be associated with atypical clinical presentation and paucibacillary disease Novel Diagnostics are needed to enhance diagnostic capacity of the traditional methods of TB diagnosis

Diagnostic Considerations for Tuberculosis Microscopy: Fluorescence microscopy is 15% more sensitive than Ziehl Neelsen stains Rapid Molecular test: Xpert MTB/RIF has been endorsed by World Health Organization as a first-line diagnostic test in all HIV patients Urine LAM in CD4<50 Culture: Liquid or Solid culture remain the gold standard for TB diagnosis Chest radiograph: mainly for triage and screening presumptive TB patients. It maybe diagnostic for miliary TB

Respiratory samples: sputum, bronchoalveolar lavage and gastric aspirates; Non respiratory samples: cavitary fluids, LNs, bone samples, CSF, pus, urine (PLoS ONE, 12(4): e0176186)

Homogenous opacities in both paracardiac areas and lower zones sparing the periphery. There are associated air bronchograms. The cardiac borders are obscured by the infiltrates. Conclusion: Bilateral pneumonic conolidation (Rightmiddle lobe & lingula segment) PCP/PKS

Bilateral cotton – wool fluffy infiltrates sparing only the left apical region. Conclusion: widespread pneumonia with alveolar pattern. ? Fungal, ?Bacterial infection. PCP/ PKS

Bilateral heterogenous infiltrates in both lower lung fields, sparing the periphery. Conclusion: bilateral pneumonia PTB and PCP likely. PCP/PKS

Kaposi Sarcoma

Pulmonary Kaposi’s Sarcoma Kaposi's sarcoma (KS) is a vascular tumor of blood vessels and lymph nodes KS is the most common and life threatening cancer in Sub-Saharan Africa Human Herpes Virus 8 is a necessary and essential factor in the development of KS (Nwabudike SM et al. Case Reports in Infectious Diseases 2016)

Of 6292 PLWH 215 (3.4%) had AIDS associated KS Advanced KS and absence of chemotherapy was associated with mortality There should be early ART and chemotherapy in these students (Journal of the International AIDS Society 2010, 13:23)

Diagnosis of AIDS-Associated KS Histological Visualization of typical violaceous endobronchial lesions HHV 8 detected in BAL of 80% patients with pulmonary KS

Fungal Pneumonias

Burden of Fungal Infections in AIDS Fungal Infections are a common cause of pulmonary disease in AIDS but are underdiagnosed It may be difficult to differentiate colonization from infection Fungal infections in HIV present insidiously but may progress to severe disease if untreated Important differential diagnosis for smear negative disease in HIV Specific diagnosis is crucial to ensure appropriate treatment Require intensive treatment followed by prolonged maintenance therapy

Common Fungal Pathogens in AIDS patients Opportunistic Pneumocystis Pneumonia Pulmonary Cryptococcosis Pulmonary Candidiasis Pulmonary Aspergillosis Endemic Histoplasmosis Emmonsiosis (Emergomyces Africanus) Penicillosis (Asia)

Microbiological Diagnosis Direct microscopy and staining for fungal elements – cheap and useful Culture and identification – more sensitive than microscopy Histopathological diagnosis – visualization of fungal elements within tissues Immunologic and Biochemical – complement fixing antibodies; fungal antigen detection in blood (Histoplasmosis, Cryptococcosis) Aspergillus Galactomannan Antigen Test Molecular Diagnostics – PCR-based assays (Candida, Aspergillus, P.jiroveci) (Semin Respir Crit Care Med. 2011 December ; 32(6): 663–672)

Median CD4 count 23 cells/µL 132 smear negative patients underwent bronchoscopy and bronchoalveolar lavage Median CD4 count 23 cells/µL 15(11%) grew Cryptococcus neoformans (none were suspected to have pulmonary cryptococcosis at enrollment) 9(60%) were alive at 6 months, 4 died and 2 were lost to follow up (J Acquir Immune Def, 2011; 54(3): 269-274)

An estimate of the prevalence of pulmonary aspergillosis in HIV-positive Ugandan in patients diagnosed as smear-negative pulmonary tuberculosis. Page ID, Worodria W, Andama A, Ayakaka I, Kwizera R, Davis L, Huang L, Richardson M, Denning WR 39 HIV+ with abnormal CXR; Mean 35 years Median CD4 109 cells/µL Aspergillus specific IgG was positive in 26% (vs 2% in controls) 40% with a positive result died within two months of diagnosis

Summary Respiratory disorders are a common manifestation of AIDS Community Acquired Pneumonia and Tuberculosis occur with increasing frequency in patients with AIDS Opportunistic Bacterial, Fungal Infections; and Malignancies occur in individuals with AIDS and are frequently underdiagnosed Current diagnostic tests are inadequate More novel and validated diagnostic are needed that target locally relevant pathogens causing lung disease

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