Management of Community-Acquired Pneumonia in Immunocompromised Adults: A Consensus Statement Regarding Initial Strategies

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“Management of Community-Acquired Pneumonia in Immunocompromised

Adults: A Consensus Statement Regarding Initial Strategies”
Article in Chest · June 2020

DOI: 10.1016/j.chest.2020.05.598
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1
[ Chest Infections Guidelines and Consensus Statements ] 56
2 57
3 58
4 59
5 60
6
7
Treatment of Community-Acquired 61
62
8
9
Pneumonia in Immunocompromised 63
64
10
11
Adults 65
66
12 A Consensus Statement Regarding Initial Strategies 67
13 68
14 Q31 Julio A. Ramirez, MD; Daniel M. Musher, MD; Scott E. Evans, MD; Charles Dela Cruz, MD; Kristina A. Crothers, MD; 69
15 Chadi A. Hage, MD; Stefano Aliberti, MD; Antonio Anzueto, MD; Francisco Arancibia, MD; Forest Arnold, DO; 70
16
Elie Azoulay, MD; Francesco Blasi, MD; Jose Bordon, MD; Steven Burdette, MD; Bin Cao, MD; Rodrigo Cavallazzi, MD; 71
17 72
James Chalmers, MD; Patrick Charles, MD; Jean Chastre, MD; Yann-Erick Claessens, MD; Nathan Dean, MD;
18 73
Xavier Duval, MD; Muriel Fartoukh, MD; Charles Feldman, MD; Thomas File, MD; Filipe Froes, MD;
19 74
Stephen Furmanek, MPH; Martin Gnoni, MD; Gustavo Lopardo, MD; Carlos Luna, MD; Takaya Maruyama, MD;
20 75
21 Rosario Menendez, MD; Mark Metersky, MD; Donna Mildvan, MD; Eric Mortensen, MD; Michael S. Niederman, MD; 76
22 Mathias Pletz, MD; Jordi Rello, MD; Marcos I. Restrepo, MD; Yuichiro Shindo, MD; Antoni Torres, MD; 77
Q1 Q32 Grant Waterer, MD; Brandon Webb, MD; Tobias Welte, MD; Martin Witzenrath, MD; and Richard Wunderink, MD
23 78
24 79
25 80
26 BACKGROUND: Community-acquired pneumonia (CAP) guidelines have improved the treat- 81
27 ment and outcomes of patients with CAP, primarily by standardization of initial empirical 82
28 83
therapy. But current society-published guidelines exclude immunocompromised patients.
29 84
30 RESEARCH QUESTION: There is no consensus regarding the initial treatment of immuno- 85
31
Q6 compromised patients with suspected CAP. 86
32 STUDY DESIGN AND METHODS: This consensus document was created by a multidisciplinary 87
33 panel of 45 physicians with experience in the treatment of CAP in immunocompromised 88
34 patients. The Delphi survey methodology was used to reach consensus. 89
35 90
36
RESULTS: The panel focused on 21 questions addressing initial management strategies. The panel
91
37 achieved consensus in defining the population, site of care, likely pathogens, microbiologic 92
38 workup, general principles of empirical therapy, and empirical therapy for specific pathogens. 93
39 This document offers general suggestions for the initial treatment of the
INTERPRETATION: 94
40 immunocompromised patient who arrives at the hospital with pneumonia. 95
41 CHEST 2020; -(-):--- 96
42 97
43 Q7 KEY WORDS: community-acquired pneumonia; immunocompromised; pneumonia 98
44 99
45 100
46 101
47 ABBREVIATIONS: CAP = community-acquired pneumonia; CMV = Veterans Puget Sound Health Care System (Dr Crothers), University of 102
48 Q2 cytomegalovirus; MDR = multiple drug resistant; MRSA = methicillin- Washington, Seattle WA; the Thoracic Transplant Program (Dr Hage), 103
resistant Staphylococcus aureus; NTM = nontuberculous mycobacteria; Indiana University, Indianapolis, IN; the Department of Pathophysi-
49 PCP = Pneumocystis jirovecii pneumonia; TMP-SMX = trimethoprim- ology and Transplantation (Drs Aliberti and Blasi), University of 104
50 sulfamethoxazole; TNF = tumor necrosis factor Milan, and Fondazione IRCCS Cà Granda Ospedale Maggiore Poli- 105
51 AFFILIATIONS: From the Division of Infectious Diseases (Drs Ram- clinico, Respiratory Unit and Cystic Fibrosis Adult Center, Milan, Italy; 106
irez, Arnold, and Gnoni, and Mr Furmanek), University of Louisville, the South Texas Veterans Health Care System (Drs Anzueto and
52 Restrepo), Audie L. Murphy Memorial Veterans Hospital, and Uni- 107
Louisville, KY; the Baylor College of Medicine and Michael E. DeBakey
53 VA Medical Center (Dr Musher), Houston, TX; the Department of versity of Texas Health, San Antonio, TX; the Pneumology Service (Dr 108
54 Pulmonary Medicine (Dr Evans), University of Texas MD Anderson Arancibia), Instituto Nacional del Tórax and Clínica Santa María, 109
Cancer Center, Houston, TX; Pulmonary, Critical Care and Sleep Santiago de Chile, Chile; the Medical ICU (Dr Azoulay), Saint-Louis
55 Teaching Hospital, Assistance Publique-Hôpitaux de Paris 110
Medicine (Dr Dela Cruz), Yale University, New Haven, CT; the
chestjournal.org 1
PGL 5.6.0 DTD CHEST3287_proof 1 August 2020 7:02 am EO: CHEST-19-3007

111 Guidelines for the treatment of patients with 166
112 (APHP), Paris, France; the Section of Infectious Diseases (Dr Bordon), community-acquired pneumonia (CAP) have been 167
113 Providence Health Center, Washington, DC; the Wright State Uni- 168
versity Boonshoft School of Medicine (Dr Burdette), Dayton, OH; the
published by medical societies from several countries.
114 169
Department of Pulmonary and Critical Care Medicine (Dr Cao), These guidelines have improved the treatment and
115 Center of Respiratory Medicine, National Clinical Research Center for 170
outcomes of patients with CAP, primarily by
116 Respiratory Diseases, China-Japan Friendship Hospital, Beijing, China; 171
the Division of Pulmonary, Critical Care, and Sleep Disorders Medi- standardization of initial empirical therapy. But current
117 172
cine (Dr Cavallazzi), University of Louisville, Louisville, KY; the society-published CAP guidelines exclude
118 Scottish Centre for Respiratory Research (Dr Chalmers), School of 173
119 Medicine, Ninewells Hospital and Medical School, Dundee, UK; the immunocompromised patients.1-3 174
Department of Infectious Diseases (Dr Charles), Austin Health and Immunocompromised patients have been excluded from
120 175
Department of Medicine, University of Melbourne, Australia; the
121 Service de Médecine Intensive-Réanimation (Dr Chastre), Hôpital La guidelines because of their need for complex, often 176
122 Pitié-Salpêtrière, Sorbonne Université, APHP, Paris, France; the individualized, treatment, the expanded spectrum of 177
Department of Emergency Medicine (Dr Claessens), Centre Hospi-
123 potential pathogens, and their exclusion from the large 178
talier Princesse Grace, Monaco; the Intermountain Medical Center and
124 the University of Utah (Dr Dean), Salt Lake City, UT; the UMR 1137, prospective studies of antibiotic efficacy used to support 179
125 IAME, INSERM (Dr Duval), and CIC 1425, Hôpital Bichat-Claude guideline recommendations. 180
Bernard, APHP, Paris, France; the Service de Médecine Intensive
126 181
Réanimation (Dr Fartoukh), Hôpital Tenon, APHP, and APHP, Sor-
127 bonne Université, Faculté de Médecine Sorbonne Université, Paris, The number of immunocompromised people at risk for 182
128 France; the Department of Internal Medicine (Dr Feldman), Faculty of CAP is increasing, due to (1) longer survival of patients 183
Health Sciences, University of the Witwatersrand, Johannesburg, South
129 with cancer, and recipients of organ transplants; (2) 184
Africa; the Infectious Disease Section (Dr File), Northeast Ohio
130 Medical University and Infectious Disease Division, Summa Health, better recognition of immunocompromising conditions; 185
131 Akron, OH; the ICU, Chest Department (Dr Froes), Hospital Pulido (3) additional risk groups, such as those receiving novel 186
Valente-Centro Hospitalar Universitário Lisboa Norte, Lisbon,
132 immune-modulating therapies for nonmalignant 187
Portugal; the Fundación del Centro de Estudios Infectológicos (Dr
133 Lopardo), Buenos Aires, Argentina; the Pulmonary Diseases Division 188
diseases; and (4) approval of newer immunomodulatory
134 (Dr Luna), Universidad de Buenos Aires, Buenos Aires, Argentina; the 189
Department of Respiratory Medicine (Dr Maruyama), National Hos- agents. It is estimated that 3% of the adult population of
135 190
pital Organization Mie National Hospital, Tsu, Japan; the Pneumology the United States is immunosuppressed.4
136 Department (Dr Menendez), La Fe University and Polytechnic Hos- 191
137 pital, La Fe Health Research Institute, Valencia, Spain; the Division of Immunocompromising conditions are present in 192
138
Pulmonary, Critical Care and Sleep Medicine and Center for Bron- approximately 20% to 30% of hospitalized patients with 193
chiectasis Care (Dr Metersky), University of Connecticut Health,
139 Farmington, CT; the Icahn School of Medicine at Mount Sinai (Dr
CAP.5-7 194
140 Mildvan), New York, NY; the Department of Medicine (Dr Morten- 195
141
sen), University of Connecticut Health Center, Farmington, CT; Pul- Frequently, the initial treatment of pneumonia in 196
monary and Critical Care (Dr Niederman), New York Presbyterian/ immunocompromised patients may not occur in
142 Weill Cornell Medical Center and Weill Cornell Medical College, New 197
143 York, NY; the Institute for Infectious Diseases and Infection Control specialized tertiary care centers with advanced expertise 198
(Dr Pletz), Jena University Hospital, Jena, Germany; the Centro de in their care. Rather, immunocompromised patients
144 199
Investigacion Biomedica en Red de Enfermedades Respiratorias (Dr
145 Rello), Instituto de Salud Carlos III, and Infections Area, Vall d’Hebron with symptoms of lower respiratory tract infection often 200
146 Institute of Research, Barcelona, Spain; the Department of Respiratory present first to general hospitals to be treated by ED 201
Medicine (Dr Shindo), Nagoya University Graduate School of Medi-
147 physicians, internists, or hospitalists. These general 202
cine, Nagoya, Japan; the Servei de Pneumologia (Dr Torres), Hospital
148 Clinic, Universitat de Barcelona. Barcelona, CIBERES, Spain; the conditions are identical to those motivating the initial 203
149 School of Medicine (Dr Waterer), University of Western Australia,
impetus for guidelines to treat CAP; namely, the 204
Perth, Australia; the Division of Infectious Diseases and Clinical
150 205
Epidemiology (Dr Webb), Intermountain Healthcare, Salt Lake City, frequency of the condition and the presentation of
151 UT and Division of Infectious Diseases and Geographic Medicine, 206
patients in many different health-care settings
152 Stanford Medicine, Palo Alto, CA; the German Center for Lung 207
Research (Dr Welte), Biomedical Research in Endstage and Obstruc- throughout the community.
153 208
tive Lung Disease Hannover (BREATH) Clinic of Pneumology,
154 Hannover Medical School, Hannover, Germany; the Division of Pul- 209
Early and adequate empirical treatment of CAP in the
155 monary Inflammation and Department of Infectious Diseases and 210
Respiratory Medicine (Dr Witzenrath), Charité-Universitätsmedizin general population is associated with decreased
156 211
Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and morbidity and mortality, and the authors attempt here
157 Berlin Institute of Health, Berlin, Germany; and Pulmonary and 212
158 Critical Care (Dr Wunderink), Northwestern University Feinberg to facilitate application of these same principles to 213
School of Medicine, Chicago, IL. patients at high risk of CAP-related complications due
159 214
FUNDING/SUPPORT: Sponsored by the International Respiratory
160
Q3 Q4 Infection Society. to preexisting immune dysfunction. The approaches 215
161 CORRESPONDENCE TO: Julio A. Ramirez, MD, Division of Infectious
suggested in this document are based on an extensive 216
162 Diseases, University of Louisville, 501 E Broadway, Ste 100, Louisville, review of the literature and on the collective experience 217
Q5 KY 40202; e-mail: j.ramirez@louisville.edu
163 of the authors. A challenge in reviewing the CAP 218
Copyright Ó 2020 Published by Elsevier Inc under license from the
164 literature on the immunocompromised host is that most 219
American College of Chest Physicians.
165 220
DOI: https://doi.org/10.1016/j.chest.2020.05.598 publications evaluate outcomes of antimicrobial therapy
2 Guidelines and Consensus Statements [ -#- CHEST - 2020 ]

221 for patients in whom the pathogen causing CAP has the immune system that are affected by the underlying 276
222 been identified. No large, prospective clinical studies disease and/or medical therapy. In this document we 277
223 278
comparing different empirical therapies in attempt to develop a unifying approach to simplify a
224 279
immunocompromised patients exist. very complex topic, involving a heterogeneous
225 280
population. The objective of this document is to suggest
226 Susceptibility to specific infections varies widely in 281
an approach to the initial treatment of
227 immunocompromised patients and depends both on the 282
228
immunocompromised patients with suspected CAP. 283
degree of immune suppression and the components of
229 284
230 285
231 286
232
Methods opportunity to revise their earlier answers, considering the
287
anonymized replies of other members of the panel.
233 The Delphi survey methodology was used to reach consensus. After a 288
full review of the English literature on the topic of treatment of CAP in After the participants answered the third round of all questions, the
234 289
the immunocompromised patient, the Delphi questions used in the range of the answers decreased significantly and it was considered
235 that the group had reached consensus. At that point, a prefinal 290
survey were developed (Table 1). The following 5-point Likert scale
236 was used to evaluate agreement or disagreement with each proposed manuscript was created and submitted to all participants for final 291
237 answer: strongly disagree (1), disagree (2), neutral (3), agree (4), comments and agreement ratings. After the final comments were 292
238 strongly agree (5). It was considered that a consensus was reached incorporated, the manuscript was produced. Further details 293
once more than 75% of participants agreed or strongly agreed with a regarding the Delphi survey methodology and rounds are to be
239 294
particular suggestion. found in e-Appendix 1 in the online article.
240 295
241 In each round of the Delphi survey, questions regarding the treatment Statistical Analysis 296
242 of CAP in the immunocompromised patient were submitted to all 45 At each round of the survey, the mean and SD of agreement based on 297
Q8 participants in the consensus process. To anonymously record
243 the Likert scale for each question were calculated. To evaluate the level 298
participant responses and comments, a survey was developed using of agreement or disagreement for each question in a manner that
244 Research Electronic Data Capture (REDCap), which allowed 299
incorporated both the mean and SD, a t-statistic for each question
245 participants to answer with their level of agreement with the was calculated. The t-statistic was used to identify which questions 300
246 suggestion, and to write specific comments regarding the had the least amount of agreement or the most controversy. 301
247 management suggested by the group. After each round, all responses Agreement was visualized by bar charts, and final agreement was 302
were summarized and an anonymized summary of all the comments reported as the percentage of participants who responded as Agree
248 303
was produced and sent to each participant. Participants had the or Strongly Agree.
249 304
250 305
251 306
Results longer survival of patients with serious conditions and
252 307
253
an expanding armamentarium of biological agents result 308
A. Definition of Population
254 in expanding populations of at-risk individuals. Using 309
Question 1: Which patients with CAP should be this approach, the most common acquired conditions
255 310
considered immunocompromised? that qualify a patient as being immunocompromised are
256 311
257 We suggest that patients with CAP should be considered a malignancy that suppresses immune responses (such 312
258 to be immunocompromised if they have an underlying as lymphoma or leukemia) and advanced HIV infection 313
259
disease or medical treatment that alters the immune (CD4 T-lymphocyte count < 200 cells/mL). The most 314
260 frequent treatments that qualify a patient as being 315
system to the point that they are at elevated risk of
261 immunocompromised include glucocorticoids, therapies 316
pneumonia not only by common organisms but also by
262 317
Q9 uncommon avirulent or opportunistic organisms. that suppress B-cell or T-cell responses, chemotherapy
263 318
for malignancy that causes neutropenia, conventional
264 No consensus exists regarding which patients should be 319
disease-modifying antirheumatic drugs, and biological
265 320
formally considered immunocompromised. Our agents used to treat a broad range of rheumatologic,
266 321
pragmatic approach is to consider patients to be dermatologic, GI, and autoimmune diseases. Notably,
267 322
immunocompromised if they are at elevated risk of some agents (eg, ibrutinib, alemtuzumab, or fludarabine)
268 323
269
pneumonia not only by common organisms but also by have persistent immunosuppressive effects, long after 324
270 uncommon avirulent or opportunistic organisms. active treatment is discontinued. Conditions indicating 325
271 Several practical aspects of meeting this definition that patients are immunocompromised are listed in 326
272 include the need for comprehensive microbiologic Table 2.8-13 327
273 testing, the need to alter empirical antimicrobial therapy, 328
274 and the need for adjunctive therapy. Even using this Most patients who develop CAP have one or more 329
275 more restrictive definition, medical advances supporting comorbid condition(s) that increase their susceptibility 330
chestjournal.org 3

331 TABLE 1 ] Questions Addressing Initial Treatment Strategies for Immunocompromised Adults With Community- 386
332 Acquired Pneumonia Q24
387
333 A. Definition of Population 388
334 389
Question 1: Which patients with CAP should be considered immunocompromised?
335 390
B. Site of Care
336 391
Question 2: Which immunocompromised patients with CAP should be admitted to the hospital?
337 392
338 C. Likely Pathogens 393
339 Question 3: What pathogens should be considered “core respiratory pathogens” in patients with CAP who are 394
340 immunocompromised? 395
341 Question 4: What pathogens should be considered beyond the core respiratory pathogens in patients with CAP who are 396
343 D. Microbiological Workup 398
344 Question 5: What microbiological studies should be done in hospitalized patients with CAP who are immunocompromised? 399
345 Question 6: When should bronchoscopy with bronchoalveolar lavage be performed in hospitalized patients with CAP who are Q25 400
347 Question 7: What microbiological studies can be obtained in bronchoalveolar lavage fluid in hospitalized patients with CAP 402
348 who are immunocompromised? 403
349 E. Empiric Therapy: General Principles 404
350 Question 8: What empiric therapy should be started in hospitalized patients with CAP who are immunocompromised? 405
351 406
Question 9: In which patients with CAP who are immunocompromised should empiric therapy be extended beyond the core
352 respiratory pathogens? 407
353 Question 10: What role does the severity of pneumonia play in the selection of initial empiric therapy? 408
354 409
F. Empirical Therapy: Specific Pathogens
355 410
Question 11: In which immunocompromised patients should the initial empiric therapy be extended to cover the possibility
356 411
of CAP due to MRSA?
357 412
358 413
of drug-resistant gram-negative bacilli, including Pseudomonas aeruginosa?
359 414
360 415
of CAP due to multidrug-resistant (MDR) gram-negative bacilli?
361 416
362 of CAP due to Pneumocystis jirovecii pneumonia (PCP)? 417
363 418
364 of CAP due to Aspergillus? 419
365 420
366 of CAP due to Mucorales? 421
367 422
368 of CAP due to Nocardia? 423
369 424
370 of CAP due to varicella-zoster virus? 425
371 Question 19: In which immunocompromised patients should the initial empiric therapy be extended to cover the possibility 426
372 of CAP due to cytomegalovirus? 427
374 of CAP due to Mycobacterium tuberculosis? 429
376 of CAP due to parasites? 431
377 432
CAP ¼ community-acquired pneumonia; MRSA ¼ methicillin-resistant Staphylococcus aureus.
378 433
379 434
380 to infection. From this perspective, patients with patients with this degree of immune dysfunction are 435
381 common comorbid conditions such as diabetes, typically infected with the same spectrum of 436
382 chronic lung disease, liver disease, kidney disease, or organisms that cause CAP in younger or healthier 437
383 even those who are elderly and frail, can be adults, and their treatment is covered in the current 438
384 considered relatively immunocompromised. However, CAP guidelines. 439
385 440

441 TABLE 2 ] Patient Conditions Qualifying Patients as Immunocompromised 496
442 497
Patient Condition References
443 498
Primary immune deficiency diseases .
444 499
445 Active malignancy or malignancy within 1 y of CAP, excluding patients with localized skin cancers or early-stage . 500
cancers (eg, stage 1 lung cancer)
446 501
447 Receiving cancer chemotherapy . 502
448 HIV infection with a CD4 T-lymphocyte count < 200 cells/mL or percentage < 14%a 8 503
449 Solid organ transplantation . 504
450 Hematopoietic stem cell transplantation . 505
451 Receiving corticosteroid therapy with a dose $ 20 mg prednisone or equivalent daily for $ 14 d or a cumulative 9, 10 506
452 dose > 700 mg of prednisoneb 507
453 Receiving biological immune modulators c
11, 12 508
454 509
Receiving disease-modifying antirheumatic drugs or other immunosuppressive drugs (eg, cyclosporin, 13
455 cyclophosphamide, hydroxychloroquine, methotrexate) 510
456 511
457 See Table 1 legend for expansion of abbreviation. 512
a
The association of HIV disease and CAP can be categorized in three levels: Level 1: Patients with a CD4 T-lymphocyte count > 500 cells/mL. These patients
458 513
are not at increased risk of CAP. Level 2: Patients with a CD4 T-lymphocyte count between 500 and 200 cells/mL. These patients are at increased risk of CAP,
459 but are not considered immunocompromised because the etiologic agents are the core CAP pathogens such as Streptococcus pneumoniae. Level 3: Patients 514
460 with a CD4 T-lymphocyte count < 200 cells/mL. These patients are at risk for CAP due to opportunistic pathogens such as Pneumocystis jirovecii. They are 515
461 considered immunocompromised patients with CAP. 516
b
In the case of patients taking steroid and who have CAP, both the daily dose and the cumulative dose of steroids should be considered. The association with
462 517
CAP can be define in three levels: Level 1: Doses # 10 mg of prednisone per day and a cumulative dose of less than 600 mg of prednisone or equivalent.
463 These patients are not at increased risk of CAP. Level 2: Doses 10 to # 20 mg of prednisone per day with a cumulative dose greater than 600 mg of 518
464 prednisone or equivalent at the time of the CAP episode. These patients are at increased risk of CAP, but are not considered immunocompromised because 519
465 the etiologic agents are the core CAP pathogens such as Streptococcus pneumoniae. Level 3: Doses $ 20 mg or more of prednisone per day with a 520
cumulative dose greater than 600 mg of prednisone or equivalent at the time of the CAP episode. These patients are at risk for CAP due to opportunistic
466 pathogens such as Pneumocystis jirovecii. They are considered immunocompromised patients with CAP. Because of the cumulative dose of at least 600 mg, 521
467 these patients need to have received steroid therapy for at least 3 to 4 wk to be considered as fulfilling this condition. 522
c
468 These drugs are used to treat a wide array of inflammatory conditions and have multiple immunologic targets. The diverse effects of these drugs include 523
interfering with cell signaling, inhibiting cytokine function, interrupting innate immunity, depleting B cells, or inhibiting T-cell activation. Specific dis-
469 524
cussion of these drugs in detail is beyond the scope of this article. However, nearly all immunomodulators carry some risk of infection. Because these
470 immunomodulating agents affect different components of the immune system, the risk for specific infections varies with the target of the 525
471 immunomodulator. 526
472 527
473 528
474 529
B. Site of Care infiltrate on chest radiography. A CT scan of the chest
475 530
Question 2: Which immunocompromised patients with will allow better definition of the extent of pulmonary
476 531
477 CAP should be admitted to the hospital? infiltrate as well as better recognition of complications of 532
478 pneumonia such as abscesses or pleural effusions. This 533
We suggest that the decision for hospitalization should be information, gained by CT imaging of the chest, may
479 534
480
based on clinical judgment having a low threshold for help in the decision regarding hospitalization. Hypoxia 535
481 hospital admission. is a particularly useful criterion to define site of care. In 536
482 nonimmunocompromised patients with CAP, blood 537
In patients with CAP who are not
483
immunocompromised, the admission decision is based oxygen saturation < 92% is considered an appropriate 538
484 threshold for hospital admission.17 539
on clinical judgment and can be supplemented by using
485 540
validated severity scores such as the Pneumonia Severity Immunocompromised patients may appear stable at the
486 541
Index or the CRB-65/CURB-65. Hospitalization of time of the initial evaluation but may deteriorate rapidly,
487 542
immunocompromised patients with CAP is based progressing in a few hours from moderately severe
488 543
primarily on clinical judgment, considering that CAP pneumonia to severe pneumonia in need of intensive
489 544
490 severity scores have not been well validated in care. Also, the increased range of potential infecting 545
491 immunocompromised patients.14-16 Because agents renders selection of any empirical regimen much 546
492 immunosuppressive drugs are known to modulate the more challenging, often requiring parenteral agents. 547
493 inflammatory response, the typical signs and symptoms Therefore, our suggestion is for a low threshold for 548
494 of CAP may be attenuated in these patients. The blunted hospitalization. If the patient is considered sufficiently 549
495 stable for outpatient care, mechanisms for close follow- 550
inflammatory response may not produce a clear
chestjournal.org 5

551 up and rapid reentry to inpatient health care should be immunocompromised host and (2) for which 606
552 available. antimicrobial therapy is available are listed in Table 4. 607
553 608
Different types of immunocompromising conditions will
554 C. Likely Pathogens 609
predispose to different types of etiologic agents. A
555 610
556
Question 3: What pathogens should be considered “core description of specific immune deficiencies and the
611
respiratory pathogens” in patients with CAP who are associated respiratory pathogens are depicted in Table 5.
557 612
Initial empirical therapy active against these respiratory
559 pathogens may be necessary only in selected patients 614
We suggest that the list of core respiratory pathogens able
560 615
to cause CAP in the immunocompromised patient should presenting with specific epidemiologic, clinical, or
561 616
be the same as those for the nonimmunocompromised. immunologic risk factors for infection due to a
562 617
particular pathogen. These risk factors and the specific
563 Immunocompromised patients are susceptible to 618
564
pathogens that are involved are discussed below. 619
infection with the same respiratory viruses and bacteria
565 620
that cause CAP in nonimmunocompromised patients. D. Microbiological Workup
566 621
We call these “core respiratory pathogens.” Common
567 Question 5: What microbiological studies should be done Q10 622
respiratory viral pathogens that cause mild upper
568 in hospitalized patients with CAP who are 623
569
respiratory tract infections in healthy adults can lead to 624
immunocompromised?
570 severe lower respiratory tract infections in 625
571 immunocompromised patients. Table 3 lists the primary We suggest a comprehensive microbiological workup with 626
572 groups of core respiratory pathogens that can cause CAP the goal to perform pathogen-directed therapy and 627
573 in immunocompromised patients.5,6,18 deescalation of therapy. 628
574 629
Question 4: What pathogens should be considered beyond A critical aspect of the treatment of these patients is an
575 630
576
the core respiratory pathogens in patients with CAP who initial microbiologic workup coupled with empirical 631
577 are immunocompromised? therapy, followed by a deescalation to therapy directed 632
578 to the causative pathogen. Deescalation of therapy is 633
We suggest to focus attention on respiratory pathogens
579 important because continuing broad-spectrum therapy 634
that may cause CAP in the immunocompromised patient
580 for the full duration of therapy is associated with 635
and for which antimicrobial therapy is available.
581 selection of multidrug-resistant organisms, increased 636
582 When considering likely etiologies of CAP beyond the risk of toxicity, drug-drug interactions, and impaired 637
583 core respiratory pathogens, it is important to focus antimicrobial stewardship for the entire community. As 638
584 attention on organisms that are amenable to the primary way to perform deescalation therapy is by 639
585 640
antimicrobial treatment. Common respiratory knowing which pathogen is causing the pneumonia, a
586 641
pathogens that (1) may cause CAP in the comprehensive microbiologic workup is critically
587 642
588 643
589 644
TABLE 3 ] Core Respiratory Pathogens That May Cause Community-Acquired Pneumonia in the Immunocom-
590 promised Patient 645
591 646
Gram-Positive Bacteria Gram-Negative Bacteria “Atypical” Bacteria Respiratory Viruses
592 647
593 Streptococcus Haemophilus influenzae Legionella Influenza virus 648
pneumoniae pneumophila
594 649
595 Staphylococcus aureus Moraxella catarrhalis Chlamydophila Parainfluenza virus 650
(MSSA) pneumoniae
596 651
597 Streptococcus Enterobacteriaceae (eg, Klebsiella species, Mycoplasma Coronavirus 652
pyogenes Escherichia coli) pneumoniae
598 653
Other streptococci Coxiella burnetii Respiratory
599 654
syncytial virus
600 655
Rhinovirus
601 656
602 Adenovirus 657
603 Human 658
604 metapneumovirus 659
605 660
MSSA ¼ methicillin-susceptible Staphylococcus aureus.

661 TABLE 4 ] Common Respiratory Pathogens in Addition to Core Respiratory Pathogensa That Can Cause 716
662 Community-Acquired Pneumonia in the Immunocompromised Patient and for Which Antimicrobial 717
663 Therapy Is Available 718
664 Bacteria Mycobacteria Viruses Fungi Parasites 719
665 Enterobacteriaceae (including those Mycobacterium Cytomegalovirus Pneumocystis Toxoplasma
720
666 producing ESBL, and also CRE) TB jirovecii gondii 721
667 Nonfermenting gram-negative bacilli (eg, Nontuberculous Herpes simplex Aspergillus Strongyloides 722
668 Pseudomonas or Acinetobacter) mycobacteria virus species stercoralis 723
669 MRSA Varicella-zoster Mucorales 724
670 virus species 725
671 Nocardia species Histoplasma 726
672 species 727
673 Rhodococcus equi Cryptococcus 728
674 species 729
675 Blastomyces 730
676 species 731
677 Coccidioides 732
678 species 733
679 734
CRE ¼ carbapenemase-producing Enterobacteriaceae; ESBL ¼ extended-spectrum b-lactamase. See Table 1 legend for expansion of other abbreviation.
680 a 735
As described in Table 3.
681 736
682 737
683 important. Another reason to perform broad Preferably, bronchoscopy with BAL should be done 738
684 microbiologic studies is that treatment of opportunistic early so that initial empirical therapy does not alter the 739
685 pathogens is complex and often complicated by culture results. If the bronchoscopy can be done 740
686 toxicities and drug-drug interactions. promptly, a short delay before initiating antibiotic 741
687 therapy may be acceptable, given improved culture yield. 742
688 The extent of the microbiologic workup should be 743
In general, the more immunocompromised the host, the
689 individualized, considering the presence of risk factors 744
greater the potential benefit of performing
690 and likely organisms, as well as local capabilities. The 745
bronchoscopy with BAL.
691 field of diagnostic microbiologic techniques has 746
692 experienced significant progress. The development of If the etiology of CAP may be defined on the basis of 747
693 rapid diagnostic tests using new molecular techniques initial radiography and point-of-care diagnostic 748
694 and sophisticated new laboratory methods, such as testing, the small, but nevertheless clear risk associated 749
695 750
matrix-assisted laser desorption ionization-time of flight with bronchoscopy with BAL may outweigh the
696 751
(MALDI-TOF) mass spectrometry, is reshaping the benefit.30
697 752
clinical microbiology laboratory as well as our ability to
698 Question 7: What microbiological studies can be obtained 753
identify etiologic agents of CAP in
699 in bronchoalveolar lavage fluid in hospitalized patients 754
700
immunocompromised patients.19 A list of common 755 Q12
with CAP who are immunocompromised?
701 microbiologic studies with relevant clinical 756
702 considerations is depicted in Table 6.20-29 We suggest that microbiological studies in 757
703 bronchoalveolar lavage should be ordered according to 758
Question 6: When should bronchoscopy with
704 the presence of risk factors for particular pathogens. 759
bronchoalveolar lavage be performed in hospitalized
705 760
706
patients with CAP who are immunocompromised? In some institutions a fixed panel of tests is routinely 761
707 performed on BAL from immunocompromised patients 762
We suggest that the decision to perform a bronchoscopy
708Q11 with CAP. In other institutions, the tests are ordered 763
or bronchoalveolar lavage should be individualized.
709 considering the presence of clinical, radiographic, and 764
710 Bronchoscopy with BAL will be useful even in a immunologic risk factors for specific organisms. 765
711 clinically unstable patient if the patient is at risk for Table 731-35 lists microbiologic studies that can be done 766
712 infection with multiple opportunistic pathogens and an on BAL or tissue from a transbronchial lung biopsy 767
713 experienced team is available to perform the procedure. together with relevant clinical considerations. 768
714 769
715 770
chestjournal.org 7

771 TABLE 5 ] Specific Immune Deficiencies and Associated Respiratory Pathogens 826
772 827
Specific Immune Deficiency Unique Respiratory Pathogen Associations
773 828
Neutropenia Pseudomonas aeruginosa, Stenotrophomonas maltophilia,
774 829
other Enterobacteriaceae, Streptococcus mitis, Q26
775 Staphylococcus aureus, Nocardia species, Aspergillus and
830
776 other hyaline molds (Scedosporium, Fusarium), yeast-like 831
777 fungi (Trichosporon), Mucorales species, dimorphic fungi 832
778 AIDS Pneumocystis jirovecii, Streptococcus pneumoniae, 833
779 Mycobacterium TB, M. avium-intracellulare complex, and 834
780 other nontuberculous mycobacteria, Histoplasma 835
capsulatum, Coccidioides, Bartonella, Rhodococcus,
781 836
Toxoplasma gondii, Cryptococcus neoformans,
782 Cryptosporidium, Nocardia, Talaromycosis marneffei, 837
783 Paracoccidioides, Burkholderia, cytomegalovirus, 838
784 Strongyloides 839
785 T-cell depletion (anti-thymocyte globulin, alemtuzumab) Pneumocystis jirovecii, Streptococcus pneumoniae, 840
786 Mycobacterium TB, M. avium-intracellulare complex, and 841
787 other nontuberculous mycobacteria, Aspergillus and other 842
hyaline molds, Mucorales species, varicella-zoster, herpes Q27
788 843
simplex, cytomegalovirus, Histoplasma capsulatum,
789 Coccidioides, Bartonella species, Toxoplasma gondii, 844
790 Cryptococcus neoformans, Nocardia, Legionella, 845
791 Strongyloides 846
792 Hypogammaglobulinemia (common variable Respiratory viruses (influenza, respiratory syncytial virus, 847
793 immunodeficiency, multiple myeloma, therapies that human metapneumovirus, parainfluenza, adenovirus, 848
794 target CD19/20, eg, rituximab) enterovirus), encapsulated bacteria (S. pneumoniae, 849
Moraxella catarrhalis, Haemophilus influenzae, S. aureus,
795 850
Capnocytophaga, Pasteurella multocida), cytomegalovirus,
796 Pneumocystis 851
797 852
Calcineurin inhibitors (cyclosporine and tacrolimus) Legionella, Nocardia, Aspergillus and other hyaline molds,
798 Mucorales species, cytomegalovirus, endemic fungi 853
799 Antimetabolites (mycophenolate mofetil, azathioprine, 6- Cytomegalovirus, varicella, respiratory viruses (if B-cell
854
800 MP, fludarabine) impairment), Legionella, Nocardia, Aspergillus and other 855
801 hyaline molds, Mucorales species, endemic fungi 856
(Pneumocystis—fludarabine) Q28
802 857
803 Mammalian target of rapamycin inhibitors (sirolimus, Cryptococcus, Pneumocystis 858
804 everolimus) 859
805 Tumor necrosis factor inhibitors Endemic fungi, Aspergillus, Mycobacterium (tuberculous and 860
806 nontuberculous), varicella-zoster, Nocardia, Pneumocystis 861
807 Janus kinase signaling inhibitors (eg, ibrutinib, dasatinib) Pneumocystis, mold, cytomegalovirus 862
808 Corticosteroids Bacteria, esp. Pseudomonas aeruginosa, Pneumocystis 863
809 jirovecii, Staphylococcus aureus, mycobacteria, Aspergillus 864
and other hyaline molds, Mucorales species,
810 865
cytomegalovirus, varicella-zoster, herpes simplex,
811 866
Histoplasma capsulatum, Coccidioides, Cryptococcus
812 neoformans, Nocardia, Legionella, Strongyloides 867
813 Other Natalizumab (Cryptococcus), vedolizumab (Mycobacterium
868
814 TB), tocilizumab (unknown), ustekinumab (theoretical 869
815 cytomegalovirus), secukinumab (theoretical mold), 870
816 eculizumab (Pseudomonas, mold), bortezomib (varicella- 871
zoster)
817 872
818 6-MP ¼ 6-mercaptopurine. 873
819 874
820 E. Empiric Therapy: General Principles We suggest that immunocompromised patients without 875
821
Q13 Question 8: What empiric therapy should be started in any additional risk factors for drug-resistant bacteria can 876
822 hospitalized patients with CAP who are receive initial empiric therapy targeting only the core 877
823 immunocompromised? respiratory pathogens. 878
824 879
825 880

881 TABLE 6 ] Microbiologic Studies That Can Be Done in Immunocompromised Patients Hospitalized With 936
882 Community-Acquired Pneumonia 937
883 Studies References 938
884 939
Sputum samples for bacterial, mycobacterial, and fungal stains and cultures 20, 21
885 940
Comments: Sputum can be induced with inhaled isotonic or preferably hypertonic saline for certain pathogens
886 941
(eg, MTB, PCP) to avoid invasive procedures. Sputum samples can be tested by PCR for detection of MTB or
887 PCP 942
888 943
Nasopharyngeal swab with multiplex PCR for respiratory viruses 22, 23
889 944
Comments: A negative nasopharyngeal PCR result does not rule out viral pneumonia. If the suspicion is high,
890 945
perform the PCR on bronchoscopic samples. The finding of a virus by PCR does not rule out bacterial
891 infection 946
892 947
Nasopharyngeal swab with multiplex PCR for atypical bacteria .
893 948
Comments: Atypical pathogens such as Legionella, Chlamydophila, or Mycoplasma can also be identified in
894 oropharyngeal samples
949
895 950
Nasal PCR for MRSA .
896 951
Comments: Use in conjunction with a respiratory sample. A negative MRSA nasal PCR result, the absence of
897 952
gram-positive cocci in clusters on Gram stain, and a negative MRSA respiratory culture make MRSA
898 pneumonia extremely unlikely 953
899 954
Blood cultures times two (at least), 30 min apart 24, 25
900 955
Comments: If there is a port or central line or PICC line, to define the presence of line infection, perform blood
901 956
cultures from a peripheral vein and from the catheter lumens at the same time to calculate “time to
902 positivity.” The separation of samples over time improves bacterial detection in the case of intermittent 957
903 bacteremia 958
904 Urinary antigen for Streptococcus pneumoniae . 959
905 Comments: The recent administration of pneumococcal vaccine (within days) will produce a positive urinary 960
906 antigen result for Streptococcus pneumoniae 961
907 Urinary antigen for Legionella 26 962
908 963
Comments: Detects only Legionella pneumophila serotype 1. Other gram-negative bacteria may generate a
909 false positive test result. Obtain respiratory samples for culture and PCR to detect other species of 964
910 Legionella or serotypes if clinically indicated 965
911 Urinary antigen for Histoplasma capsulatum . 966
912 Comments: Very useful for disseminated disease. Cross-reaction with blastomycosis
967
913 968
Serum antigen for Cryptococcus neoformans .
914 969
Comments: A serum cryptococcal antigen test may produce a negative result for a patient with documented
915 970
cryptococcal pneumonia
916 971
Serum galactomannan antigen 27
917 972
Comments: Aspergillus cell wall contains the polysaccharide galactomannan. Also elevated in Fusarium,
918 973
Penicillium, blastomycosis, and histoplasmosis. False positive results may occur with IVIG, transfusions,
919 974
and some b-lactam antibiotics
920 975
Serum 1,3-b-D-glucan 27
921 976
Comments: b-D-Glucan is a cell component of several fungi. It screens for Aspergillus species, Candida Q29
922 977
species, PCP, and other fungi. It does not detect mucormycosis. False positive results may occur with IVIG,
923 hemodialysis with cellulose, albumin, infections with Pseudomonas, and some b-lactam antibiotics 978
924 979
Swabs of vesicular or ulcerated skin lesions for viral PCR and cultures .
925 980
Comments: A positive PCR result for HSV or VZV from skin lesions is highly correlated with herpes or varicella-
926 981
zoster pneumonia
927 982
Biopsy of skin lesion for microbiology and pathology .
928 983
Comments: Sample must be sent to microbiology and pathology for stains and cultures for viruses, bacteria,
929 984
mycobacteria, fungi, and parasites
930 985
Viral load for CMV (PCR) 28
931 986
932 Comments: Obtain only if clinical suspicion is high. CMV reactivation is common in acute illness, and the 987
presence of copies of CMV in plasma does not necessarily indicate invasive disease. On the other hand, the
933 988
absence of viremia makes CMV pneumonitis less likely
934 989
935 (Continued) 990
chestjournal.org 9

991 TABLE 6 ] (Continued) 1046
992 1047
Studies References
993 1048
Viral load for adenovirus 29
994 1049
995 Comments: Obtain only if clinical suspicion is high. 1050
996 Serology for histoplasmosis, coccidioidomycosis, and blastomycosis 27 1051
997 Comments: Fungal serology is not generally recommended in immunosuppressed patients because they fail 1052
998 to generate an adequate antibody response to infection 1053
999 1054
CMV ¼ cytomegalovirus; HSV ¼ herpes simplex virus; IVIG ¼ IV immunoglobulin; MTB ¼ Mycobacterium TB; PCP ¼ Pneumocystis jirovecii pneumonia;
1000 PCR ¼ polymerase chain reaction; PICC ¼ peripherally inserted central line catheter; VZV ¼ varicella-zoster virus. See Table 1 legend for expansion of other 1055
1001 abbreviation. 1056
1002 1057
1003 1058
Although immunocompromised hosts may have unique availability of point-of-care tests, severity of disease at
1004 1059
1005
immunologic risk and often more frequent nosocomial presentation, and use of prophylactic therapy for a 1060
1006 contact and antibiotic exposure, many particular opportunistic pathogen. 1061
1007 immunocompromised patients admitted with CAP do 1062
The need for empirical therapy of opportunistic
1008 not have any additional risk factors for drug-resistant 1063
pathogens will continue to evolve as more point-of-care
1009 bacteria (eg, methicillin-resistant Staphylococcus aureus 1064
tests are developed for rapid diagnosis. Empirical
1010 [MRSA], Pseudomonas). For these patients, we suggest 1065
therapy beyond core respiratory pathogens may not be
1011 initial empirical antimicrobial therapy targeting the core 1066
1012
necessary if the patient is clinically stable and the local 1067
respiratory pathogens described in Table 3. In this group
1013 setting allows for rapid microbiologic diagnostic tests. 1068
of patients, the initial empirical antibacterial therapy
1014 1069
would be the same as the initial empirical therapy for Question 10: What role does the severity of pneumonia
1015 1070
hospitalized patients with CAP who are not play in the selection of initial empirictherapy?
1016 1071
immunocompromised.1 Additional empirical treatment
1017 We suggest that the presence of severe pneumonia can be 1072
1018
beyond the core respiratory pathogens should be 1073
used as an indication to start empiric therapy for
1019 considered according to the presence of risk factors for 1074
resistant gram-positive and gram-negative organisms,
1020 drug-resistant or opportunistic pathogens and is 1075
followed by rapid deescalation if no multidrug-resistant
1021 discussed in the sections below. 1076
pathogen is identified.
1022 1077
Question 9: In which patients with CAP who are
1023 Severity of illness is not by itself an accurate predictor of 1078
1024
immunocompromised should empirical therapy be 1079
drug resistance or opportunistic infection in pneumonia.
1025 extended beyond the core respiratory pathogens? 1080
For example, Streptococcus pneumoniae is capable of
1026 causing life-threatening septic shock, whereas invasive 1081
Q14 We suggest to extend empiric therapy beyond core
1027 1082
respiratory pathogens when (1) risk factors for drug- pulmonary aspergillosis may present with an indolent,
1028 1083
resistant organisms or opportunistic pathogens are progressive course.
1029 1084
present and (2) the delay in empiric antimicrobial
1030 The impact of severe pneumonia on empirical therapy is 1085
1031
therapy will place the patient at increased risk of 1086
the critical need to start early with an appropriate
1032 mortality. 1087
antimicrobial therapy, because an initial inadequate
1033 antibiotic spectrum has been identified as an 1088
In addition to initial empirical treatment for core
1034 1089
respiratory pathogens, we suggest broader initial independent risk factor for mortality in CAP. Given this
1035 1090
coverage when the following factors are met: (1) A circumstance, the presence of severe pneumonia or
1036 1091
resistant bacterium or an opportunistic pathogen is pneumonia requiring ICU care can be used as a
1037 1092
1038 suspected on the basis of the presence of risk factors threshold to start empirical therapy for resistant gram- 1093
1039 from findings on history or physical examination, positive organisms (eg, MRSA) and resistant gram- 1094
1040 laboratory results, and/or imaging patterns; and (2) negative organisms (eg, Pseudomonas). 1095
1041 waiting for microbiologic identification of the suspected 1096
1042 pathogen will significantly delay initiation of F. Empirical Therapy: Specific Pathogens 1097
1043 antimicrobial therapy and may increase the risk of Question 11: In which immunocompromised patients 1098
1044 mortality. Other considerations for extending initial should the initial empiric therapy be extended to cover the 1099
1045 1100
empirical therapy beyond core pathogens include possibility of CAP due to MRSA?

1101 We suggest that initial empiric therapy to cover for MRSA activity against P. aeruginosa, such as piperacillin- 1156
1102 should be started in patients with a history of tazobactam or a carbapenem, should be used as core 1157
1103 1158
colonization or infection with MRSA in the previous therapy. However, ceftazidime, which has no reliable
1104 1159
12 months. activity against S. pneumoniae, should not be used as
1105 1160
monotherapy.43
1106 In patients with a history of colonization or infection 1161
1107 with MRSA in the previous 12 months, initial empirical 1162
Question 13: In which immunocompromised patients
1108 therapy should cover the possibility of infection due to 1163
should the initial empiric therapy be extended to cover the
1109 MRSA. There are other risk factors reported in the 1164
possibility of CAP due to multidrug-resistant (MDR)
1110 1165
literature for MRSA infection such as prior antibiotic gram-negative bacilli?
1111 1166
use, recent hospitalization, hemodialysis, or wound care,
1112 We suggest that in patients with a recent history of 1167
but if the local prevalence of MRSA is low these risk
1113 1168
factors will each have a low positive predictive value and colonization or infection with MDR gram-negative
1114 1169
should not be used to trigger empirical anti-MRSA bacilli, the initial empiric therapy should cover the
1115 1170
therapy.36-40 On the other hand, a single patient who possibility of infection due to the colonizing MDR gram-
1116 1171
accumulates many of these risk factors may have a high negative bacilli.
1117 1172
1118 likelihood of CAP due to MRSA. Vancomycin or In patients with a recent history of colonization or 1173
1119 linezolid are the first line for initial empirical therapy. In infection with MDR gram-negative bacilli such as 1174
1120 1175
regions with a high prevalence of MRSA, some members extended-spectrum b-lactamase-producing
1121 of the panel will start empirical anti-MRSA therapy in 1176
Enterobacteriaceae, carbapenemase-producing
1122 patients requiring ICU admission. A negative MRSA 1177
Enterobacteriaceae, MDR Pseudomonas, or MDR
1123 1178
result by nasal polymerase chain reaction (PCR), Acinetobacter, the initial empirical therapy should
1124 1179
absence of gram-positive cocci in clusters on Gram’s cover the possibility of infection with the colonizing
1125 1180
staining, and a negative MRSA respiratory culture can MDR gram-negative bacilli. A knowledge of the local
1126 1181
1127
be used to deescalate anti-MRSA therapy. susceptibility profile for gram-negative bacilli and the 1182
1128 Question 12: In which immunocompromised patients most recent susceptibility profile of the colonizing 1183
1129 MDR gram-negative bacilli will help in the selection 1184
1130 of empirical therapy for these organisms with difficult- 1185
possibility of drug-resistant gram-negative bacilli,
1131Q15 to-treat resistance. For empirical therapy of MDR 1186
including Pseudomonas aeruginosa?
1132 1187
gram-negative bacilli, b-lactam antibiotics such as
1133 We suggest that initial empiric therapy for 1188
piperacillin-tazobactam or imipenem may have to be
1134 1189
immunocompromised patients should cover resistant changed to newer b-lactam antibiotics that have better
1135 gram-negative bacilli, including Pseudomonas 1190
activity against some of the MDR bacteria. In these
1136 1191
aeruginosa, if there is a history of colonization or patients, consideration should be given to the addition
1137 1192
infection with a resistant gram-negative bacilli in the of ceftazidime-avibactam, ceftolozane-tazobactam, or
1138 1193
prior 12 months, previous hospitalization with exposure meropenem-vaborbactam. Adding a polymyxin such
1139 1194
1140
to broad-spectrum antibiotics, the presence of a as colistin to a traditional b-lactam is a possibility 1195
1141 tracheostomy, neutropenia, or a history of pulmonary when other agents are not available. In patients 1196
1142 comorbidity. treated empirically with these broad-spectrum agents, 1197
1143 we strongly emphasize an extended microbiologic 1198
History of colonization or infection with a drug-resistant
1144 workup and prompt deescalation of therapy if 1199
gram-negative bacillus in the previous 12 months,
1145 1200
previous hospitalization with exposure to broad- appropriate.
1146 1201
1147
spectrum antibiotics, the presence of a tracheostomy, Question 14: In which immunocompromised patients 1202
1148 neutropenia, a history of pulmonary comorbidity (eg, should the initial empiric therapy be extended to cover the 1203
1149 cystic fibrosis, bronchiectasis, or recurrent exacerbations possibility of CAP due to Pneumocystis jirovecii 1204
1150 of COPD requiring glucocorticoid and antibiotic use) pneumonia (PCP)? 1205
1151 have been reported in the literature to increase the risk 1206
1152 of resistant gram-negative bacilli.37-42 Patients with any We suggest initial empiric therapy should be extended to 1207
1153 of these risk factors should be considered for initial cover the possibility of PCP in patients with diffuse, 1208
1154 empirical therapy against resistant gram-negative bacilli bilateral, interstitial infiltrates or alveolar opacities and 1209
1155 1210
including P. aeruginosa. b-Lactam antibiotics with who are not receiving PCP prophylaxis, and either (1) an
chestjournal.org 11

1211 TABLE 7 ] Microbiologic Studies in BAL Fluid or Tranbronchial Lung Biopsy 1266
1212 1267
Study Reference
1213 1268
Bacterial Gram stain and culture
1214 1269
1215 Comments: A negative stain and culture of MDR pathogens (eg, MRSA) can be used for deescalation of therapy 1270
unless antibiotics have been given for > 48 h
1216 1271
1217 MRSA PCR 1272
1218 Comments: A negative PCR for MRSA can be used for deescalation of anti-MRSA therapy unless antibiotics 31 1273
1219 have been given for > 48 h 1274
1220 AFB stains and culture for tuberculous and nontuberculous mycobacteria 1275
1221 Comments: If positive AFB stain, nucleic acid amplification (NAA) tests allows for rapid diagnosis. NAA test can 20 1276
1222 be performed if the AFB stain is negative and the suspicion of disease is high 1277
1223 Nocardia stains and culture 1278
1224 Comments: AFB stain may be weakly positive 1279
1225 Fungal stains and culture 1280
1226 1281
Comments: Because Aspergillus can colonize the airways, positive stains or culture of Aspergillus species from 27
1227 respiratory samples do not necessarily indicate disease 1282
1228 PCP stains and PCR
1283
1229 1284
Comments: In patients with PCP, the sensitivity of staining is higher in HIV-infected patients when compared 32
1230 with HIV-uninfected patients. A positive PCR may occur in patients colonized with PCP. In non-HIV patients, 1285
1231 a negative PCR can be used to discontinue anti-PCP therapy 1286
1232 Respiratory viral panel with multiplex PCR 1287
1233 1288
Comments: Viruses can be detected in BAL by PCR in a patient with a negative nasopharyngeal swab PCR for 22, 23
1234 the same virus 1289
1235 1290
Atypical pathogens panel with multiplex PCR
1236 1291
Comments: A positive PCR is considered diagnostic for atypical pneumonia because pathogens such as
1237 Legionella, Chlamydophila, or Mycoplasma rarely colonize the airway
1292
1238 1293
Galactomannan antigen
1239 1294
Comments: The cell wall of Aspergillus contains the polysaccharide galactomannan. Other fungi that contain 27
1240 1295
galactomannan include Histoplasma capsulatum, Penicillium species, and Fusarium species. False positive
1241 levels may occur in BAL samples with some b-lactam antibiotics 1296
1242 1297
Aspergillus PCR
1243 1298
Comments: The high sensitivity of PCR produces a high negative predictive value, making the diagnosis 27
1244 1299
unlikely with a negative test
1245 1300
(1,3)-b-D-Glucan
1246 1301
Comments: It is considered a poor screening tool for the diagnosis of invasive fungal infections because of its 27
1247 1302
low positive predictive value
1248 1303
CMV PCR
1249 1304
1250 Comments: Quantitative PCR analysis in BAL fluid may help to differentiate between CMV pneumonia (high 33 1305
viral load) vs CMV pulmonary shedding without pneumonia (low viral load), but cutoff levels are not defined
1251 1306
Cellular analysis
1252 1307
1253 Comments: A predominantly inflammatory cellular pattern in the BAL with neutrophil pleocytosis can be used 34, 35 1308
as a predictor of bacterial etiology
1254 1309
1255 Histopathology 1310
1256 Comments: Routine hematoxylin and eosin staining, special stains, and culture for viruses, bacteria, 1311
1257 mycobacteria, fungi, and parasites 1312
1258 1313
1259 1314
1260 1315
1261
Q16 HIV host who is newly diagnosed, or not on antiretroviral In these patients we suggest the addition of 1316
1262 therapy, or with CD4 counts less than 200 cells/mL (or a trimethoprim-sulfamethoxazole (TMP-SMX) to the 1317
1263 percentage lower than 14%) or (2) non-HIV hosts with initial regimen. The recommended dosage for TMP- 1318
1264 severely impaired cell-mediated immunity (eg, SMX is 15 to 20 mg/kg/d of the trimethoprim 1319
1265
Q17 glucocorticoids with cytotoxic agents). component orally or IV, given in three or four divided 1320

1321 doses.44 The dose of TMP-SMX is the same for PCP in voriconazole antifungal prophylaxis. In these patients we 1376
1322 the HIV-infected patient and PCP in the suggest liposomal amphotericin as part of the initial 1377
1323 1378
immunocompromised non-HIV-infected patient. empirical regimen at dosages of 5 to 7.5 mg/kg daily.48
1324 1379
Adjunctive glucocorticoids are recommended for HIV- In patients intolerant to amphotericin, empirical therapy
1325 1380
infected patients with room air PaO2 < 70 mm Hg and/ with isavuconazole at an initial dosage of 200 mg every
1326 1381
or an alveolar-arterial (A-a) oxygen gradient $ 8 h can be used as an alternative.47 Voriconazole does
1327 1382
1328
35 mm Hg.44 Corticosteroids are not beneficial in HIV- not cover mucormycosis, and therefore it is not 1383
1329 negative patients with PCP.45 suggested as initial empirical therapy. 1384
1330 1385
Question 15: In which immunocompromised patients Question 17: In which immunocompromised patients
1331 1386
should the initial empiric therapy be extended to cover the should the initial empiric therapy be extended to cover the
1332 1387
possibility of CAP due to Aspergillus? possibility of CAP due to Nocardia?
1333 1388
1334 We suggest that empiric therapy should cover the 1389
We suggest that empirical therapy should include the
1335 1390
possibility of pneumonia due to filamentous fungi such as possibility of Nocardia infection in patients with heart,
1336 1391
Aspergillus in patients with cancer and chemotherapy lung, liver, or hematopoietic stem cell transplant with
1337 1392
with severe and prolonged neutropenia and a pneumonia and evidence for a lung or brain abscess,
1338 1393
radiographic nodular pattern surrounded by a halo of and who have not been receiving prophylaxis with
1339 1394
1340
ground-glass attenuation and/or cavitation. TMP-SMX. 1395
1341 1396
Voriconazole is considered the first-line treatment for
1342 In these patients we suggest the addition of TMP-SMX 1397
patients with documented invasive aspergillosis, but we
1343 to the initial empirical therapy at a dosage of 15 mg/kg/ 1398
do not suggest empirical voriconazole because these
1344 d of the trimethoprim component IV in three or four 1399
patients are also at risk for other filamentous fungi
1345 divided doses.49 Resistance of Nocardia species to TMP- 1400
1346
resistant to voriconazole (eg, those causing 1401
SMX is a rare event.50 If TMP-SMX is contraindicated,
Q18
1347 mucormycosis).46 In these patients we suggest empirical 1402
linezolid also has excellent activity and can be
1348 therapy with liposomal amphotericin at dosages of 5 to 1403
considered for empirical therapy until susceptibilities are
1349 7.5 mg/kg daily. In patients intolerant to amphotericin, 1404
known.50 If initial treatment already contains a drug
1350 empirical therapy with isavuconazole at an initial dosage 1405
with activity against Nocardia species (eg, linezolid or
1351 of 200 mg every 8 h can be used as an alternative.47 1406
imipenem), empirical addition of TMP-SMX is not
1352 1407
1353 Patients treated with tumor necrosis factor (TNF) requested. However, TMP-SMX is the drug of choice for 1408
1354 inhibitors, such as etanercept, infliximab, or definite treatment. 1409
1355 adalimumab, are also at risk of fungal pneumonia.11,12 1410
1356 In these patients we suggest an aggressive diagnostic 1411
1357 workup, and treat if a fungus is identified. In the 1412
possibility of CAP due to varicella-zoster virus?
1358 treatment of these patients it is important to discontinue 1413
1359 the use of the anti-TNF drug at the time of diagnosis of We suggest that empiric therapy be extended to cover the 1414
1360 1415
pneumonia to improve the level of immunity of the possibility of CAP due to varicella-zoster virus in patients
1361 1416
patient. with bilateral reticulonodular infiltrates who also have a
1362 1417
vesicular rash.
1363 Question 16: In which immunocompromised patients 1418
1364 should the initial empiric therapy be extended to cover the In these patients we suggest the addition of IV acyclovir, 1419
1365 possibility of CAP due to Mucorales? 10 to 15 mg/kg IV every 8 h, to the initial empirical 1420
1366 1421
regimen.51
1367 We suggest that empiric therapy should cover the 1422
1368 possibility of pneumonia due to filamentous fungi such as Question 19: In which immunocompromised patients 1423
1369 Mucorales in patients with cancer and chemotherapy should the initial empiric therapy be extended to cover the 1424
1370 with severe and prolonged neutropenia and a possibility of CAP due to cytomegalovirus? 1425
1371 radiographic nodular pattern, or a reverse halo sign, or 1426
1372 We suggest that empiric therapy be extended to cover the 1427
pleural effusion.
1373 possibility of CAP due to cytomegalovirus in patients with 1428
1374 Empirical therapy for Mucorales is especially important bilateral interstitial pneumonia after a recent lung 1429
1375 when fungal infection is suspected in a patient receiving transplant or hematopoietic stem cell transplant. 1430
chestjournal.org 13

1431 In these patients we suggest the addition of ganciclovir or patients with high and prolonged dosages of 1486
1432 to the initial regimen at a dosage of 5 mg/kg IV every 12 corticosteroids (eg, prednisone $ 20 mg/d, or its 1487
1433 1488
h, with dose adjustment for renal dysfunction.52 equivalent, for longer than 1 month) in combination
1434 1489
Elevated plasma cytomegalovirus (CMV) viral loads are with cytotoxic agents. Patients receiving this type of
1435 1490
frequent in patients with CMV pneumonitis, but this immune-suppressing therapy, and also those with
1436 1491
finding alone is not sufficient for diagnosis.53 In lung secondary bacteremias, may not have an elevated
1437 1492
1438
transplant recipients, CMV PCR viral load in BAL is a eosinophil count suggesting a parasitic infection. 1493
1439 superior diagnostic tool than plasma CMV viral load.54 Therapy with ivermectin is recommended for patients 1494
1440 with hyperinfection syndrome.55 1495
1441 1496
should the initial empiric therapy be extended to cover the Toxoplasma pneumonia occurs due to reactivation of
1442 1497
Q19 possibility of CAP due to Mycobacterium tuberculosis? latent infection in (1) patients with HIV infection that is
1443 1498
1444
newly diagnosed, and not undergoing antiretroviral 1499
We suggest not to start empiric therapy to cover the
1445 therapy or with CD4 counts less than 100 cells/mL; or (2) 1500
possibility of CAP due to Mycobacterium TB.
1446 patients with defects in cell-mediated immunity due to 1501
1447 Pulmonary infections due to mycobacteria, such as TB, high and prolonged doses of corticosteroids in 1502
1448 are common in patients treated with TNF inhibitors and combination with cytotoxic agents. Therapy with 1503
1449 patients with long-term high-dose steroids.11 But in the pyrimethamine and sulfadiazine is recommended for 1504
1450 case of suspected mycobacterial pneumonia we do not patients with Toxoplasma pneumonia.44 1505
1451 suggest treating the patient with empirical therapy. We 1506
1452 We think that in these patients the risk-to-benefit ratio 1507
suggest carrying out the indicated microbiologic studies
1453 of expanding empirical therapy for parasitic infections, Q211508
and beginning treatment once the pathogen has been
1454 or waiting to define which patients have a parasitic 1509
identified. We think that in these patients the risk-to-
1455 infection, favors waiting for microbiologic results and 1510
Q20 benefit ratio of expanding empirical therapy with
1456 treat only the patients with a proven parasitic infection. 1511
1457
multiple mycobacterial drugs, vs waiting to define which 1512
1458 patients have a mycobacterial infection, is in favor of 1513
1459 waiting for microbiologic results and treating them Discussion 1514
1460 specifically. In this document we have developed general suggestions 1515
1461 for the initial treatment of the immunocompromised 1516
An exception to this approach would be in patients with
1462 patient who arrives at the hospital with pneumonia. 1517
HIV infection with a history of recent exposure, who
1463 Despite our suggestions of empirical therapy for specific 1518
1464
have other clinical findings and radiographic features 1519
pathogens in specific situations, we stress the
1465 compatible with TB infection, and who present with 1520
importance of making a concerted effort to establish a
1466 severe CAP. In these patients we will start empirical 1521
rapid and accurate etiologic diagnosis and to deescalate
1467 therapy for TB pending microbiologic workup.44 1522
complex therapies once a presumptive pathogen is
1468 1523
Question 21: In which immunocompromised patients properly ruled out. It is also important to consider local
1469 1524
1470
should the initial empiric therapy be extended to cover the susceptibility patterns when selecting empirical therapy. 1525
1471 possibility of CAP due to parasites? The participants do suggest that, if evidence supports the 1526
1472 presence of infections that require highly specialized 1527
We suggest not to start empiric therapy to cover CAP due
1473 management (eg, cytomegalovirus or Mucorales), after 1528
to parasites.
1474 initial therapy is begun, prompt transfer to a tertiary 1529
1475 Parasites that can produce CAP in the care facility should be strongly considered. Transfer to a 1530
1476 immunocompromised host include Strongyloides specialized center may not be necessary if experienced 1531
1477 stercoralis and Toxoplasma gondii.55,56 pulmonary and infectious disease specialists are 1532
1478 available to participate in management. 1533
1479 Pneumonia in patients with Strongyloides hyperinfection 1534
1480 syndrome may be due to invasion of lung tissue by the An important weakness of this document is the 1535
1481 filariform larvae or with gram-negative bacteremia simplification of heterogeneous conditions that affect 1536
1482 secondary to seeding of the blood from the GI tract. different arms of the immune system into a single group 1537
1483 Patients at risk of Strongyloides hyperinfection of immunocompromised patients with CAP. Another 1538
1484 syndrome include those with solid organ limitation is that we were not able to provide references 1539
1485 1540
transplantation, hematopoietic stem cell transplantation, that appropriately support several of our suggestions;

1541 hence we need to emphasize that the suggestions offered tumor necrosis factor-a agents). Clin Microbiol Infect. 2018;24(suppl 1596
1542 2):S10-S20. 1597
in this consensus are based primarily on expert opinion.
1543 13. Wolfe F, Caplan L, Michaud K. Treatment for rheumatoid 1598
arthritis and the risk of hospitalization for pneumonia:
1544 In conclusion, we have developed general suggestions associations with prednisone, disease-modifying antirheumatic 1599
1545 for the initial treatment of immunocompromised drugs, and anti-tumor necrosis factor therapy. Arthritis Rheum. 1600
2006;54(2):628-634.
1546 patients hospitalized with pneumonia. When possible, 1601
1547 14. Sanders KM, Marras TK, Chan CK. Pneumonia severity index in the 1602
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15. Carrabba M, Zarantonello M, Bonara P, et al. Severity assessment of
1549 1604
immunocompromised patients have been excluded from healthcare-associated pneumonia and pneumonia in
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prospective randomized studies of CAP treatment, there
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