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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 Delivering on the Antimicrobial Resistance (AMR) agenda is not possible without improving fungal diagnostic capabilities David W. Denning1,2, David. S. Perlin2,3, Eavan G. Muldoon1, Arnaldo Lopes Colombo2,4, Arunaloke Chakrabarti2,5, Malcolm D. Richardson2.6 and Tania C. Sorrell2,7 1 The National Aspergillosis Centre, University Hospital of South Manchester, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK 2 Global Action Fund for Fungal Infections, Geneva, Switzerland; 3 Public Health Research Institute, Rutgers Biomedical and Health Sciences, Newark, NJ, USA; 4 Division of Infectious Diseases, Universidade Federal de São Paulo, São Paulo, Brazil. 5 Center of Advance Research in Medical Mycology, Postgraduate Institute of Medical Education & Research, Chandigarh 160012, India 6 Mycology Reference Centre, Manchester; Manchester Academic Health Science Centre; University Hospital of South Manchester, Manchester and International Society for Human and Animal Mycology 7 Marie Bashir Institute for Infectious Diseases & Biosecurity, University of Sydney, Australia. *Correspondence: 34 Professor David Denning 35 National Aspergillosis Centre, Education and Research Centre, University Hospital of 36 South Manchester, Southmoor Road, Manchester M23 9LT 37 Tel.: +44 161 291 5811 38 E-mail: [email protected] 39 40 41 42 43 44 45 46 One line summary: Widespread use of accurate and sensitive fungal diagnostic testing will reduce unnecessary antibacterial and antifungal therapy Key words: Aspergillus, Candida, Pneumocystis, Histoplasma, Cryptococcus, resistance Word count: 2196 1 47 ABSTRACT 48 Antimicrobial resistance (AMR) is a major public health concern largely arising from 49 the excess use of antibacterial and antifungal drugs. Here we argue that the lack of 50 routine fungal disease diagnostic testing exacerbates the problem of antimicrobial 51 empiricism, both antibiotic and antifungal. We cite 4 common clinical situations that 52 are illustrative. 1. Accurate diagnosis of fungal sepsis in the hospital and the 53 Intensive Care Unit to reduce the use of broad-spectrum antibacterial therapy 54 administered inappropriately to patients with invasive candidiasis. 2. Failure to 55 diagnose smear-negative pulmonary ‘tuberculosis’ as chronic pulmonary 56 aspergillosis. 3. Mis-diagnosing ‘fungal asthma’ that results in unnecessary courses of 57 antibiotics instead of antifungals and missing life-threatening invasive aspergillosis in 58 COPD patients. 4. Both over- and under-treatment of Pneumocystis jirovecii 59 pneumonia in HIV positive patients. All communities should have access to non- 60 culture fungal diagnostics, which will have a substantial benefit for clinical outcome, 61 antimicrobial stewardship and AMR control. 62 63 2 64 Antimicrobial resistance (AMR) is a significant public health concern, and a major 65 threat to modern medicine (1). It is estimated that in the United States antibiotic 66 resistant infections are associated with 23,000 deaths per year (2), and that excess 67 healthcare costs are in the region of US $20-25 billion (3). Minimizing AMR has been 68 the focus of accelerating efforts with multi-pronged approaches tailored to individual 69 countries and healthcare settings. Even if the difficult task of developing new 70 antimicrobials is successful, current efforts aimed at reducing the development of 71 resistance will need to be maintained to protect these novel compounds. 72 A central tenet of controlling AMR is antibiotic stewardship, which seeks to limit 73 inappropriate antibiotic usage either by avoiding unnecessary prescribing or 74 discontinuing antibiotic therapy immediately it is not required. Within the context of 75 stewardship programs, inadequate attention has been paid to fungal infection as the 76 cause of antibacterial treatment failure. Furthermore the importance of accurate and 77 timely diagnosis of fungal infection in defeating AMR has been starkly absent from 78 policy discussions (4). Accurate diagnosis or exclusion of fungal infection impacts 79 substantially on antimicrobial usage and our ability to limit bacterial AMR. 80 Generally, physicians prescribe most antimicrobials empirically as very few 81 infections are microbiologically diagnosed in real time. Further, most infections are 82 never microbiologically documented, which matters little if the patient improves and 83 infection resolves, but leads to additional empirical antimicrobial use if the patient 84 deteriorates (5). Fungal infections are often undiagnosed and untreated, and they are 85 a frequent fatal complication (superinfection) of numerous diseases (cancer, liver, 86 respiratory and/or renal failure, sepsis, AIDS etc) that contribute to inappropriate 87 antibiotic usage. This must stop. 88 We provide four specific clinical examples where we argue for greater application 89 of existing fungal diagnostics and improved overall fungal diagnostic capability in 90 line with the recently issued ’95-95 by 2025’ Roadmap from the Global Action Fund 91 for Fungal Infections (6). 92 93 Accurate diagnosis of fungal sepsis in hospital and Intensive Care Unit (ICU) 94 Hospitalized patients, especially those in the ICU, are often inappropriately placed on 95 broad-spectrum antibiotics because fungal diseases involving Candida spp are not 96 diagnosed. Bloodstream infection and invasive candidiasis are substantially more 97 common than appreciated. Multiple factors are likely to be responsible, including 3 98 unrestrained antibiotic use, indwelling devices, increasing populations of 99 immunocompromised patients, increased renal support and others. Bloodstream 100 infections with Candida spp. have a population incidence of 1.2-26/100,000 in 101 multiple studies, with the highest rates in middle- and high-income countries, notably 102 the USA (7,8). Most (93%) of episodes are healthcare-associated (~80% as inpatients) 103 and 7% are community acquired (9). In Brazil, with a population of 194 million, 104 Candida bloodstream infections are seen in 14.9/100,000 population, or 29,000 105 people each year (10), based on prospective data obtained 10 years ago from 11 106 medical centres (11). A recent prospective study from 27 ICUs in India found a mean 107 incidence of 6.51 cases of ICU-acquired candidemia per 1,000 ICU admissions with 108 a 35-75% mortality (12). An estimated 14.3 million patients are admitted to ICUs in 109 India each year. Undoubtedly this high rate underestimates the problem, as blood 110 culture is only ~40% sensitive for invasive candidiasis (including intra-abdominal 111 candidiasis), with fluconazole and echinocandins substantially reducing the yield from 112 blood culture (13-15). It is likely therefore that the actual burden and death rate in 113 ICU exceeds 200,000 patients and ~100,000 deaths. If, as is found in other countries, 114 Candida bloodstream infection (and presumably invasive candidiasis) outside ICUs is 115 at least twice as common as in ICUs, over 600,000 patients are estimated to have 116 invasive candidiasis in India each year, with ~300,000 deaths, assuming patients are 117 treated, and many more if not. 118 In addition, a high prevalence of candidemia has been reported in children and 119 neonates in India and Latin America. Central nervous system involvement is quite 120 common in premature infants leading to a high rate of neurological sequelae (16). 121 While invasive candidiasis is strongly associated with prior bacterial infection and 122 anti-bacterial therapy, inappropriate escalation and combination antibacterial therapy 123 will typically have been administered to patients with invasive candidiasis. In one 124 large study of 444 patients with Candida bloodstream infections, 81% were exposed 125 to multiple antibacterial drugs, either concomitantly or sequentially (17) and in the 126 ICU study from India described above, 95% were already on antibiotics, usually two 127 or more (12). Early therapy of Candida bloodstream infection greatly improves 128 patient outcomes as shown in several observational studies, and even better if 129 ‘correct’ therapy is given immediately (18). 130 131 Once Candida sepsis is confirmed, antibacterial agents can usually be stopped and, if ruled out, empirical antifungal therapy can be stopped. Inflammation without 4 132 infection requires no antimicrobial therapy. Three well-validated diagnostic tools, two 133 configured for ruling out a diagnosis of invasive candidiasis, are now available - the 134 1,3 beta-D-glucan assay (19), the Candida albicans germ tube antibody test 135 (CAGTA) (serum samples) (20) and a newly FDA approved nonculture-based 136 molecular assay which is substantially more sensitive than blood culture and useful 137 for making the diagnosis Candida (EDTA blood) (21). In patients without invasive 138 candidiasis, antimicrobial stewardship programs based on such diagnostics have 139 successfully curtailed the use of antifungal therapy in the ICU without worsening 140 patient outcomes (18,22). The economics depend on the cost of diagnostic reagents 141 and testing, antifungal costs and incidence of infection (23). Overuse of antifungal 142 agents is very costly and can promote antifungal resistance, may carry toxicity and the 143 potential for numerous detrimental drug interactions (18). Modeling will be required 144 to determine the magnitude of the impact on antibacterial prescribing. What is not in 145 dispute is that patient outcomes for those with fungal infection will improve. 146 Antimicrobial stewardship programs will be even more effective if these diagnostic 147 tools, with their rapid turnaround times, are readily available (24). Widespread 148 implementation of rapid non-culture Candida diagnostics will greatly improve 149 prescribing practices for the complex hospital patient. 150 151 Mis-diagnosis of smear-negative pulmonary ‘tuberculosis’ as tuberculosis 152 Smear-negative pulmonary tuberculosis (TB) is a problematic area for clinicians 153 and policy makers. Post-tuberculous sequelae are common, poorly studied and may be 154 mistaken for active, recurrent TB (25), and it is apparent that an important under- 155 recognised issue for these patients is chronic pulmonary aspergillosis (CPA), which 156 can mimic TB presentation. Among 544 patients previously treated for TB, with a 157 residual cavity, in the UK, 34% developed precipitating antibodies to Aspergillus 158 fumigatus of whom 63% developed aspergilloma within 2 years (a late stage of 159 chronic pulmonary aspergillosis) and 42% of these patients developed hemoptysis 160 (26). Prospective studies of CPA (after treatment for TB) are otherwise lacking, but 161 conservatively an assumed rate of ~10% is likely, with ~1.2 million individuals 162 affected (26). 163 Culture of Mycobacterium tuberculosis from smear-negative patients is slow and 164 may be falsely negative. The use of new, highly sensitive, DNA detection assays (e.g. 165 Xpert MTB/RIF) directly on respiratory specimens has transformed the rapidity of 5 166 detecting positive results, but there remains a considerable proportion of unwell, 167 smear negative, PCR-negative patients. Some of these are patients who have 168 ‘relapsed’ following anti-tuberculous therapy have CPA. Those with ‘smear-negative 169 TB’ and HIV infection, have a higher mortality than smear positive patients (27), 170 probably because many do not have TB at all. It is increasingly being recognized that 171 many of these patients are chronically infected with Aspergillus spp. resulting in CPA 172 that is largely undiagnosed and untreated. 173 Weight loss, worsening cough, chest pains, dyspnea and fatigue are common to TB 174 and CPA, and the radiological abnormalities are similar (Figure 1). In studies from the 175 UK, Brazil, Korea, Iran and India, the frequency of elevated Aspergillus serum 176 antibody after TB varied upwards from 20% (28,29. Aspergillus antibody detection is 177 the key diagnostic test for CPA, and performs well (96-97% sensitivity, 92-98% 178 specificity (30,31), compared with controls. Given that CPA is a common sequel to 179 TB and has a 5-year mortality of 75-80%, it needs to be sought actively using 180 antibody testing (32). Sera from almost all patients with ‘recurrent TB’ in Iran were 181 Aspergillus antibody positive (33). Pneumocystis jirovecii DNA was identified in the 182 sputum of up to 7% of patients with smear-negative TB in Brazil and 6.7% in 183 Uganda, providing an alternative, potentially treatable diagnosis, and there are others 184 such as histoplasmosis (Figure 2) and coccidioidomycosis (5). 185 Empirical anti-tuberculous therapy is unnecessary in patients with either chronic 186 pulmonary aspergillosis or other fungal infections, as it is ineffective and exposes the 187 patient to potential toxicity. Yet, it remains the default approach for most complicated 188 TB patients. When such treatment fails, as it usually does, there is a risk that patients 189 are assumed to have multidrug resistant (MDR) TB, and the inappropriate substitution 190 of second and third line anti-tuberculous agents adds to potential toxicities and 191 healthcare costs. The size of the problem is substantial with the WHO reporting 192 2,755,870 patients with smear negative TB in 2013 (34). Aspergillus antibody 193 detection should be widely available and integrated into TB control programs with 194 CPA as post-TB sequelae emphasised. All symptomatically recurrent TB cases should 195 be screened for Aspergillus antibody. 196 197 Fungal exacerbations of asthma and chronic obstructive airways disease (COPD) 198 It is common practice in the community to treat asthma and exacerbations of 199 COPD with antibiotics and corticosteroids, although guidelines caution against 6 200 unnecessary use, especially in COPD patients (35). Most patients respond, even if the 201 exacerbation is virus-induced. Patients with moderate and severe COPD are 202 frequently admitted to hospital and have an in-hospital mortality of 6%. The majority 203 patients (>80%) are treated with antibiotics (36), although multiple guidelines advise 204 against this in the absence of purulent sputum and pulmonary infiltrates. It is now 205 well established that Aspergillus airways colonization (or infection) is strongly 206 associated with exacerbations (37). Two studies have addressed the frequency of 207 invasive aspergillosis in these patients - with a 1.3% rate in Spain (38) and a 3.9% rate 208 in southern China (39), based on sputum cultures revealing Aspergillus spp (which 209 likely under-estimates the problem as Aspergillus culture is insensitive). The 210 respective mortality rates were 65% and 43%. Most are not treated for invasive 211 aspergillosis but are treated unnecessarily with antibiotics. The scale of the problem is 212 large: In China, 87 per 10,000 people over 40 years of age (an estimated 11,858,000) 213 COPD patients were admitted to hospital in 2012 (40,41), ~462,000 may have 214 developed invasive aspergillosis and ~200,000 may have died. Presumably other 215 countries with high COPD rates such as Hungary, Ireland, and New Zealand face a 216 similar situation. 217 Asthmatics with frequent exacerbations and/or poorly controlled disease may take 218 several antibiotic courses a year and some are managed with long-term antibiotics. 219 Recently, awareness and understanding of ‘fungal asthma’ has increased and a timely 220 diagnosis and the use of antifungal therapy could substantially reduce antibiotic 221 prescriptions. Long-term antifungal therapy is efficacious in 60-80% of patients with 222 fungal asthma, notably allergic bronchopulmonary aspergillosis (ABPA) and severe 223 asthma with fungal sensitisation (SAFS) (42). Both antibiotic and corticosteroid use 224 fall with successful antifungal therapy and may reduce hospitalization. 225 Diagnosis of fungal asthma relies on total and fungal specific IgE testing, or skin 226 prick testing which is simple to do, yet not often done. Rapid antigen detection with a 227 lateral flow device might accelerate diagnosis, although no data are published on 228 utility for sputum, or on COPD patients. Few studies have addressed the role of fungi 229 in precipitating exacerbations of COPD, although culture, antigen and Aspergillus IgG 230 antibody all contribute to the diagnosis of chronic and invasive aspergillosis. 231 Failure to properly diagnose and treat fungal asthma and COPD patients with 232 Aspergillus colonisation continues to increase the inappropriate use of antibiotics (and 233 corticosteroids) among these patients. Recognition of fungal infection and/or allergy 7 234 with directed antifungal therapy would greatly reduce exacerbations, medical 235 consultations and hospital admissions. There is an urgent need to evaluate and 236 implement both fungal culture and non-culture diagnostics (Aspergillus IgE, 237 Aspergillus IgG, Aspergillus antigen and PCR) for COPD and asthma exacerbations, 238 and to diagnose fungal asthma and treat it with antifungals. 239 240 241 Making and excluding the diagnosis of Pneumocystis pneumonia in AIDS Pneumocystis pneumonia (PCP) in AIDS is often diagnosed empirically based on a 242 subacute onset of cough, breathlessness out of proportion to the radiological 243 abnormalities and subtle, bilateral chest X-ray changes, in the context of a low CD4 244 cell count (Figure 3). Co-trimoxazole (trimethoprim-sulphamethoxazole, Bactrim®, 245 Septrin®) is the most effective agent for both prevention and therapy of PCP. A low 246 dose is effective for prophylaxis, but a 3-week course of high and potentially toxic 247 doses is required for effective therapy. The differential diagnosis of PCP is broader in 248 children as bacterial pneumonia is more common. If a precise diagnosis could be 249 achieved in most cases of PCP, much inappropriate use of co-trimoxazole would be 250 prevented. 251 Rates of PCP among newly hospitalized adults with advanced HIV infection are 252 highly variable (<1% to 60%), with rising rates as gross domestic product increases 253 (43). Without adequate diagnostics available, many patients will unnecessarily 254 receive high dose co-trimoxazole with or without corticosteroids for 3 weeks. If the 255 actual number of PCP cases in patients with AIDS is 400,000, then 100,000s may be 256 given co-trimoxazole unnecessarily, with toxicity rates as high as 90% (5,44). Early 257 detection and diagnosis of PCP can help prevent unnecessary hospitalization and cost. 258 Currently bronchoscopy and microscopic examination of bronchoalveloar lavage fluid 259 is the commonest definitive means of establishing the diagnosis, with a sensitivity of 260 75-90% depending on the microscopy technique (45). Pneumocystis jirovecii is non- 261 culturable in routine laboratories and so molecular detection with PCR is commonly 262 used in Europe with a sensitivity of 95-99% (46). Pneumocystis PCR performed on 263 expectorated sputum is also effective for detecting P. jirovecii (47-49), yet 264 infrequently used. In breathless children, PCR on nasopharyngeal aspirates is 265 currently the only realistic means of establishing the diagnosis. In serum, 1,3 beta-D- 266 glucan is detectable in nearly all cases of PCP (19), and if negative, effectively rules 267 out infection. Assuming that 25% of PCP cases are mild, immediate diagnosis and use 8 268 of oral therapy will potentially avoid 100,000 admissions to hospital annually, or even 269 more if the diagnosis is ruled out and patients are not admitted for unnecessary PCP 270 therapy (5). Mild PCP responds well to treatment, and prevents progression to 271 moderate or severe infection. 272 Provision of rapid Pneumocystis diagnostics will enable early diagnosis, allow 273 discontinuation of broad spectrum antibiotics if positive and discontinuation of high 274 dose cotrimoxazole and corticosteroids if negative. Missed PCP diagnoses, obscured 275 by concurrent bacterial infection, will be minimized. Pneumocystis PCR should be 276 widely available for all respiratory samples serving large immunocompromised 277 populations and 1,3 beta-D-glucan in high volume laboratories. These diagnostics will 278 also definitively improve outcome for non-AIDS immunocompromised patients for 279 the same reasons as in AIDS. 280 281 Other clinical scenarios 282 We have not addressed multiple other clinical situations in which precise fungal 283 diagnosis could reduce inappropriate antibacterial prescribing, including cryptococcal 284 meningitis (Figure 4), overtreatment of Candida found in the respiratory tract and 285 urine which can be reduced with the use of better markers of infection, under- 286 diagnosis of invasive aspergillosis in critical care, over-treatment with antifungals of 287 febrile neutropenia in leukaemia, Aspergillus bronchitis in bronchiectasis, allergic, 288 chronic and invasive fungal sinusitis and PCP in HIV-negative patients. In all these 289 clinical settings, inappropriate antibacterial or antifungal prescribing is common, 290 through lack of adequate fungal diagnostic testing. We have also not addressed either 291 rapid detection of antifungal resistant fungi (ie Aspergillus terreus, Candida krusei) or 292 the use of diagnostics to prevent super-infection with high resistance potential fungi, 293 such as Candida glabrata or Rhizopus oryzae. Antifungal resistance is problematic in 294 some settings, demands informed prescribing, therapeutic drug monitoring and 295 development of new antifungal agents (50). 296 297 298 Conclusions Lack of availability and underuse of non-culture fungal diagnostics results in both 299 over-prescribing and prescription of unduly long courses of antibacterial agents, 300 excess empirical use of antifungal agents, and leaves many millions of patients with 301 undiagnosed fungal infections. It squanders resources. The large scale of the problem, 9 302 even in many of the world’s most advanced medical centers, compromises AMR 303 control. For many countries, Ministries of Health and private providers of healthcare 304 should be actively promoting fungal diagnosis to minimize deaths and morbidity from 305 fungal disease and such efforts will likely have a positive benefit on inappropriate 306 antibacterial usage and support stewardship programs. Public health authorities need 307 to embrace both acute and chronic fungal disease areas of considerable need and seize 308 the opportunity to improve health and preserve what remains of our antimicrobial 309 toolbox. 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337 338 339 340 341 342 343 344 345 346 347 Funding: none. Possible conflicts of interest. Dr Denning holds Founder shares in F2G Ltd a University of Manchester spin-out antifungal discovery company, in Novocyt which markets the Myconostica real-time molecular assays and has current grant support from the National Institute of Allergy and Infectious Diseases, National Institute of Health Research, NorthWest Lung Centre Charity, Medical Research Council, Astellas and the Fungal Infection Trust. He has acted as a consultant to T2 Biosystems, Astellas, Sigma Tau, Basilea and Pulmocide. In the last 3 years, he has been paid for talks on behalf of Astellas, Dynamiker, Gilead, Merck and Pfizer. He is also a member of the Infectious Disease Society of America Aspergillosis Guidelines and European Society for Clinical Microbiology and Infectious Diseases Aspergillosis Guidelines groups. Dr. Perlin serves on scientific advisory boards for Merck, Astellas, Scynexis, Matinas and Cidara, and he receives grant support from those companies, as well as from the National Institutes of Health. He is a member of the Clinical & Laboratories Standards Institute (CLSI) Antifungal Working Group. He has been a paid consultant by the Gates foundation. He is an inventor on several patents concerning detection of fungal infections and antifungal drug resistance. Dr Muldoon has delivered talks on behalf of Pfizer, Gilead, MSD and Astellas, has received an educational grant from Pfizer . Dr Colombo has received research grants from Pfizer and Astellas, medical education grants from Pfizer, MSD, United Medical and Astellas. He has also been a consultant for MSD, United Medical, and Gilead. Dr. Chakrabarti has grant support from Department of Biotechnology, Indian Council Medical Research, Government of India, from Pfizer through Asian Fungal Working Group and from MSD through Society of Indian Human and Animal Mycologist and member of European Society for Clinical Microbiology and Infectious Diseases Aspergillosis, Mucormycosis Guidelines groups 10 348 349 350 351 352 353 354 355 356 357 358 359 360 Dr Richardson is a consultant and gives talks for Basilea, Astellas, MSD, Pfizer, Gilead Sciences and Associates of Cape Cod. Dr Sorrell has received investigator driven grants from Pfizer, Merck, Gilead and have been on their advisory boards in the past. Author Bio David Denning is an infectious diseases clinician with expertise in fungal diseases. He is heavily involved in postgraduate teaching and lectures worldwide. 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Diagnostic 526 value of direct fluorescence antibody staining for detecting Pneumocystis 527 jirovecii in expectorated sputum from patients with HIV infection. Med Mycol 528 2014;52:326-30. 529 49. Nowaseb V, Gaeb E, Fraczek MG, Richardson MD, Denning DW. Frequency 530 of Pneumocystis jirovecii in sputum from HIV and TB patients in Namibia. J 531 Infect Dev Ctries. 2014;8:349-57. 532 533 50. Denning DW, Bromley MJ. Infectious Disease. How to bolster the antifungal pipeline. Science 2015;347:1414-6. 534 535 536 17 537 538 539 Figure legends 540 Chest radiograph showing bilateral upper lobe chronic pulmonary aspergillosis, easily 541 mistaken for pulmonary tuberculosis. The blue arrows show the areas of abnormality 542 in both apices – some pleural thickening and opacification, which is similar although 543 slightly more obvious to the findings in pulmonary tuberculosis. The orange arrow 544 shows the trachea pulled to one side by the contraction and fibrosis on that side. 545 Image from David Denning, all rights reserved. 546 Figure 2: 547 CT scan of the thorax showing chronic pulmonary histoplasmosis with bilateral 548 cavitary infiltrates resembling pulmonary tuberculosis, coccidioidomycosis, 549 paracoccidioidomycosis and aspergillosis. The abnormal areas are shown by arrows. 550 Image from Arnaldo Colombo, all rights reserved. 551 Figure 3: 552 Chest radiograph showing early subtle abnormalities in both lower lung fields of PCP 553 in a new diagnosis of AIDS unsuspected in a married man aged 63 years. The two 554 boxes of magnification illustrate normal lung lung (upper) and infiltrates adjacent to 555 and behind the heart and overlain by rib (lower). Similar differences between the 556 upper and lower lobes are seen in the other lung. Image from David Denning, all 557 rights reserved. 558 Figure 4: 559 An ulcerative skin lesion misdiagnosed for weeks as a bacterial infection, which 560 showed Cryptococccus neoformans on biopsy. Image from Arnaldo Colombo, all 561 rights reserved. Figure 1: 562 18