Abstract
Background
Cough is a common symptom prompting patients to seek medical care. Like patients in the general population, patients with compromised immune systems also seek care for cough. However, it is unclear whether the causes of cough in immunocompromised patients who are deemed unlikely to have a life-threating condition and a normal or unchanged chest radiograph are similar to those in persons with cough and normal immune systems.
Methods
We conducted a systematic review to answer the question: What are the most common causes of cough in ambulatory immunodeficient adults with normal chest radiographs? Studies of patients ≥ 18 years of age with immune deficiency, cough of any duration, and normal or unchanged chest radiographs were included and assessed for relevance and quality. Based on the systematic review, suggestions were developed and voted on using the American College of Chest Physicians (CHEST) methodology framework.
Results
The results of the systematic review revealed no high-quality evidence to guide the clinician in determining the likely causes of cough specifically in immunocompromised ambulatory patients with normal chest radiographs.
Conclusions
Based on a systematic review, we found no evidence to assess whether or not the proper initial evaluation of cough in immunocompromised patients is different from that in immunocompetent persons. A consensus of the panel suggested that the initial diagnostic algorithm should be similar to that for immunocompetent persons but that the context of the type and severity of the immune defect, geographic location, and social determinants be considered. The major modifications to the 2006 CHEST Cough Guidelines are the suggestions that TB should be part of the initial evaluation of patients with cough and HIV infection who reside in regions with a high prevalence of TB, regardless of the radiographic findings, and that specific causes and immune defects be considered in all patients in whom the initial evaluation is unrevealing.
Key Words: cough, evidence-based medicine, immunocompromised
Abbreviations: CHEST, American College of Chest Physicians; GRADE, Grading of Recommendations Assessment, Development, and Evaluation
Summary of Suggestions
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1.
For ambulatory immunocompromised adults with cough and normal chest radiographs, we suggest that the initial approach to the diagnosis of the cause of cough be the same as in immunocompetent persons (Ungraded Consensus-Based Statement).
-
2.
For ambulatory immunocompromised adults with cough and normal chest radiographs, we suggest that evaluations for specific diseases associated with underlying immune disorders should be conducted if the common causes of cough in the general population are excluded (Ungraded Consensus-Based Statement).
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3.
For ambulatory immunocompromised adults with cough and HIV infection who reside in areas with a high prevalence of TB, we suggest that TB should be part of the initial evaluation regardless of the radiographic findings (Ungraded Consensus-Based Statement).
Cough is a common symptom that prompts patients to seek medical care. Recognizing the importance of cough in clinical practice, the American College of Chest Physicians (CHEST) developed a consensus statement on the diagnosis and management of cough in 1998 and an updated guideline in 2006.1, 2 Patients with compromised immune systems who are not deemed to have an acute life-threating condition present with symptoms identical to the general population. The 2006 guideline included sections on cough in special populations, including patients with compromised immune systems.3 Based on the absence of high-quality evidence that identifies the likely causes of cough among these patients, there was consensus that the initial diagnostic evaluation should be the same as for otherwise healthy people and that opportunistic infections should be considered when these diagnoses that are common to all patients have been excluded. This 2006 guideline did not review the relevant literature systematically, and its recommendations were based on expert opinion. The current Cough Expert Panel concluded that performing a systematic review aimed at updating these recommendations would be useful to clinicians.
Immunodeficiency comprises a wide spectrum of disease, including but not limited to hematologic malignancy, solid tumors, immunosuppressive therapy, disorders of humoral immunity, and HIV infection.4 Many immunocompromised patients present with cough and abnormal chest radiographs.5 These patients are often seriously ill, and the initial evaluation generally focuses on establishing a diagnosis of a specific, often opportunistic, pulmonary infection. However, ambulatory immunocompromised patients present with cough in a fashion similar to that of otherwise healthy persons, with acute or chronic cough and normal chest radiographs. The panel questioned whether the most likely causes of cough in this group are similar to those in the general population (eg, upper airway cough syndrome, asthma, nonasthmatic eosinophilic bronchitis, and gastroesophageal reflux disease) or whether evaluation for opportunistic infection should be part of the initial evaluation.
Methods
The methodology of the CHEST Guideline Oversight Committee was used to select the Expert Cough Panel assigned to perform the systematic review, synthesize the evidence, and develop the recommendations and suggestions.6
Systematic Review Question
The key clinical question was systematically reviewed using the Population, Intervention, Comparator, Outcome format. The question for review was: “What are the most common causes of cough in ambulatory adults with immunodeficiency who have normal chest radiographs?” The inclusion and exclusion criteria for the review are listed in Table 1.
Table 1.
Inclusion and Exclusion Criteria for the Review
| Variable | Inclusion | Exclusion |
|---|---|---|
| Patient population | Patients (≥ 18 years of age) with any immune deficiency (see index terms) Cough of any duration Normal or unchanged chest radiograph |
Not immunodeficient No cough Chest radiograph abnormal and changed from prior images Infants and children |
| Intervention | Outcome of diagnostic evaluation | … |
| Comparator | Most common causes of cough in the general population | Exclude patients with immune deficiencies |
| Outcomes | Relative frequency of causes in the immunodeficient patient as it compares to the general population | … |
| Timing | Any duration of cough | … |
| Setting | Outpatient | Inpatient |
| Study design | Case series, prospective observational, clinical trials | Editorial, single case reports or case series of < 10 subjects, letters to the editor |
| Publications | English, French, Spanish | Other than English, French, Spanish |
| Search Terms | Multiple myeloma Leukemia (lymphatic, myelogenous) Lymphoma, Hodgkin disease Chemotherapy Immunosuppressive therapy Solid tumors Common variable immune deficiency HIV/AIDS Other |
… |
Literature Search
A systematic literature search for individual studies was conducted using the following databases: PubMed, Scopus, Cochrane Central, and the Cochrane Database of Systematic Reviews, with no date limitations (e-Appendix 1). Searches were conducted from the start of the databases until August 24, 2015, the time of the search. All searches were limited to English, Spanish, and French. Panelists reviewed the titles and abstracts of the search independently in parallel to identify potentially relevant articles based on the inclusion and exclusion criteria. Discrepancies were resolved by discussion. Studies that were deemed eligible then underwent a second round of full-text screening for final inclusion.
Quality Assessment and Data Extraction
Studies meeting all inclusion criteria were then assessed for quality and risk of bias using the appropriate tools. These tools included the Documentation and Appraisal Review Tool for systematic reviews,7 the Cochrane Risk of Bias Tool for randomized controlled trials,8 or the Risk of Bias Tool for Cohort Studies.9 Relevant data from each study were then extracted into structured evidence tables.
Grading the Evidence and Development of Recommendations
Grading of Recommendations Assessment, Development, and Evaluation (GRADE) evidence profiles were planned to guide the overall quality of the body of evidence based on five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias.6 The quality of the evidence for the outcome was rated as high, moderate, or low. The writing group then drafted recommendations if there was sufficient evidence. Recommendations would be graded using the CHEST grading system, based on the strength of the recommendation (either strong or weak) and a rating of the overall quality of the body of evidence. When there is insufficient evidence but guidance is still warranted, a weak suggestion can be developed and an “Ungraded Consensus-Based Statement” replaces the grade. For a recommendation or suggestion to be accepted, it had to be voted on during a Delphi process by 75% of the eligible cough panelists and achieve ratings of “strongly agree” or “agree” by 80% of the voting panelists.
Results
The search retrieved 2,180 documents, which the panelists then reviewed by title and abstract. The panel selected a total of 44 studies for full-text review. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for the search and study selection is presented in e-Figure 1. After applying all inclusion and exclusion criteria to the 44 studies, no study was identified as eligible.
Discussion
This systematic review revealed no studies that fulfilled our criteria on which to base a recommendation to guide the clinician on whether the initial steps in the diagnostic algorithm in ambulatory immunocompromised adult patients with cough and normal chest radiographs are different from those in persons with intact immune systems. The “recommendations” in the 2006 guideline were re-evaluated and abandoned based on adherence to current methodology. Rather, we offer “suggestions” based on an expanded list of search terms, systematic review, and application of GRADE methodology.
Nevertheless, the panel suggests that clinicians consider common diagnoses that explain cough in immunocompromised patients, regardless of a normal chest radiograph. The sensitivity of the radiograph in detecting pulmonary infection is limited, especially when the immune system is incapable of mounting a normal inflammatory response.5, 10 For example, HIV-infected patients with TB often present with cough and normal chest radiographs, especially when there is severe immunocompromise and residence in regions with a high prevalence of TB.11 In a study of 334 consecutive HIV-infected adults with cough of ≥ 2 weeks' duration who were admitted to a single hospital in Uganda, 54 had normal chest radiographs.12 The most common diagnoses were pulmonary TB in 24 patients (44%), unknown diagnosis in 19 patients (35%), pulmonary aspergillosis in three patients (6%), and pulmonary cryptococcosis in two patients (4%). Four patients had two simultaneous respiratory infections. Patients with CD4-positive lymphocyte counts ≤ 50 cells/μL were more likely to have normal radiographs than were others with higher counts.
Noninfectious disorders may also cause cough with normal radiographs in specific clinical situations. For example, obliterative bronchiolitis typically occurs up to a year after bone marrow transplantation; these patients generally present with cough and dyspnea, often with normal chest radiographs.13, 14 Some patients with cancer, cough, and normal chest radiographs are ultimately diagnosed with endobronchial metastasis on bronchoscopy, such as Kaposi sarcoma associated with AIDS.15, 16
Suggestions
-
1.
For ambulatory immunocompromised adults with cough and normal chest radiographs, we suggest that the initial approach to the diagnosis of the cause of cough be the same as in immunocompetent persons (Ungraded Consensus-Based Statement).
-
2.
For ambulatory immunocompromised adults with cough and normal chest radiographs, we suggest that evaluations for specific diseases associated with an underlying immune disorder should be conducted if the common causes of cough in the general population are excluded (Ungraded Consensus-Based Statement).
-
3.
For ambulatory immunocompromised adults with cough and HIV infection who reside in areas with a high prevalence of TB, we suggest that TB should be part of the initial evaluation regardless of the radiographic findings (Ungraded Consensus-Based Statement).
Future Studies to Consider to Close the Gaps in Knowledge
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•
Prospective studies should be performed to determine the spectrum and frequency of causes of acute, subacute, and chronic cough in ambulatory immunodeficient adult patients as well as whether the causes are similar or different than in immunocompetent patients.
-
•
Prospective studies should be performed to determine if the spectrum and frequency of causes of acute, subacute, and chronic cough in ambulatory immunodeficient adult patients is different in patients with different types and severity of immune defects and geographic factors.
-
•
Prospective studies should be performed to determine the best diagnostic algorithm for diagnosing the causes of acute, subacute, and chronic cough in ambulatory immunodeficient adult patients.
Conclusions
A consensus of the panel suggested that the initial diagnostic algorithm for ambulatory patients with cough of any duration should be similar to that for immunocompetent persons but that the context of the type and severity of the immune defect, geographic location, and social factors be considered. The panel also suggested that TB should be part of the initial evaluation of patients with HIV infection who reside in regions with a high prevalence of TB, regardless of the chest radiographic findings.
Acknowledgments
Author contributions: M. J. R. and M. S. were the topic editors for this article and developed the key question using the Population, Intervention, Comparator, Outcome (PICO) format in collaboration with R. S. I. and C. F. B. I. was the appointed methodologist and was among the investigators who conducted the systematic review that formed the basis for the suggestions. M. J. R. wrote the first draft; B. I., M. N., C. F., and R. S. I. reviewed and contributed to subsequent versions.
Financial/nonfinancial disclosures: None declared.
Collaborators: Todd M. Adams, MD (Webhannet Internal Medicine Associates of York Hospital, Moody, ME), Kenneth W. Altman, MD, PhD (Baylor College of Medicine, Houston, TX), Alan F. Barker, MD (Oregon Health & Science University, Portland, OR), Surinder S. Birring, MBChB, MD (Division of Asthma, Allergy, and Lung Biology, King’s College London, Denmark Hill, London, England), Fiona Blackhall, MD, PhD (University of Manchester, Department of Medical Oncology, Manchester, England), Donald C. Bolser, PhD (College of Veterinary Medicine, University of Florida, Gainesville, FL), Sidney S. Braman, MD, FCCP (Mount Sinai Hospital, New York, NY), Christopher Brightling, MBBS, PhD, FCCP (University of Leicester, Glenfield Hospital, Leicester, England), Priscilla Callahan-Lyon, MD (Adamstown, MD), Anne B. Chang, MBBS, PhD, MPH (Royal Children’s Hospital, Queensland, Australia), Andréanne Coté, MD (Institut universitaire de cardiologie et de pneumologie de Québec [IUCPQ], Quebec, QC, Canada), Terrie Cowley (The TMJ Association, Milwaukee, WI), Paul Davenport, PhD (Department of Physiological Sciences, University of Florida, Gainesville, FL), Satoru Ebihara, MD, PhD (Department of Rehabilitation Medicine, Toho University School of Medicine, Tokyo, Japan), Ali A. El Solh, MD, MPH (University at Buffalo, State University of New York, Buffalo, NY), Patricio Escalante, MD, MSc, FCCP (Mayo Clinic, Rochester, MN), Anthony Feinstein, MPhil, PhD (Sunnybrook Health Sciences Centre, Toronto, ON, Canada), Stephen K. Field, MD (University of Calgary, Calgary, AB, Canada), Dina Fisher, MD, MSc (University of Calgary, Respiratory Medicine, Calgary, AB, Canada), Cynthia T. French, PhD, FCCP (UMass Memorial Medical Center, Worcester, MA), Peter Gibson, MBBS (Hunter Medical Research Institute, New South Wales, Australia), Philip Gold, MD, MACP, FCCP (Loma Linda University, Loma Linda, CA), Anthony Harnden, MBChB, MSc (University of Oxford, Oxford, England), Adam T. Hill, MBChB, MD (Royal Infirmary and University of Edinburgh, Edinburgh, Scotland), Richard S. Irwin, MD, Master FCCP (UMass Memorial Medical Center, Worcester, MA), Peter J. Kahrilas, MD (Feinberg School of Medicine, Northwestern University, Chicago, IL), Karina A. Keogh, MD (Mayo Clinic, Rochester, MN), Kefang Lai, MD, PhD (First Affiliated Hospital of Guangzhou Medical College, Guangzhou, China), Kaiser Lim, MD (Mayo Clinic, Rochester, MN), J. Mark Madison, MD, FCCP, (UMass Memorial Medical Center, Worcester, MA), Mark A. Malesker, PharmD, FCCP (Creighton University School of Pharmacy and Health Professions, Omaha, NE), Stuart Mazzone, PhD, FCCP (University of Queensland, Queensland, Australia), Alex Molassoitis, PhD, MSc, RN (Hong Kong Polytechnic University, Hong Kong, China), M. Hassan Murad, MD, MPH (Mayo Clinic, Rochester, MN), Mangala Narasimhan, DO, FCCP (Hofstra-Northwell Health, Manhasset, NY), Huong Q. Nguyen, PhD, RN (Kaiser Permanente, Pasadena, CA), Peter Newcombe, PhD (School of Psychology University of Queensland, Queensland, Australia), John J. Oppenheimer, MD (University of Medicine and Dentistry of New Jersey, Rutgers University, Morristown, NJ), Marcos I. Restrepo, MD, MSc, FCCP (South Texas Veterans Health Care System, San Antonio), Mark Rosen, MD, Master FCCP (Icahn School of Medicine at Mount Sinai, New York, NY), Bruce Rubin, MEngr, MD, MBA (Virginia Commonwealth University, Richmond, VA), Jay H. Ryu, MD, FCCP (Mayo Clinic, Rochester, MN), Jaclyn Smith, MBChB, PhD (University of Manchester, Manchester, England), Susan M. Tarlo, MBBS, FCCP (Toronto Western Hospital, Toronto, ON, Canada), Julie Turmel, PhD (Quebec Heart and Lung Institute, Laval University, Quebec), Anne E. Vertigan, PhD, MBA, BAppSc (SpPath) (John Hunter Hospital, New South Wales, Australia), Gang Wang, MD, PhD (Sichuan University, West China Hospital, Chengdu, China), Miles Weinberger, MD, FCCP (University of Iowa Hospitals and Clinics, Iowa City, IA), and Kelly Weir, MsPath (Menzies Health Institute Queensland/Griffith and Gold Coast, Australia).
Other contributions: We thank other panelists and peer reviewers in the development process for this article.
Endorsements: This guideline has been endorsed by the American College of Allergy, Asthma, and Immunology (ACAAI), Asian Pacific Society for Respirology (APSR), Canadian Thoracic Society (CTS), and Irish Thoracic Society (ITS).
Role of sponsors: CHEST was the sole supporter of these guidelines, this article, and the innovations addressed within.
Additional information: The e-Appendix and e-Figure can be found in the Supplemental Materials section of the online article.
Footnotes
DISCLAIMER: American College of Chest Physician guidelines are intended for general information only, are not medical advice, and do not replace professional medical care and physician advice, which always should be sought for any medical condition. The complete disclaimer for this guideline can be accessed at http://www.chestnet.org/Guidelines-and-Resources/Guidelines-and-Consensus-Statements/CHEST-Guidelines.
FUNDING/SUPPORT: CHEST was the sole supporter of these guidelines, this article, and the innovation addressed within.
Contributor Information
Mark J. Rosen, Email: markjrosenmd@gmail.com.
CHEST Expert Cough Panel:
Todd M. Adams, Kenneth W. Altman, Alan F. Barker, Surinder S. Birring, Fiona Blackhall, Donald C. Bolser, Sidney S. Braman, Christopher Brightling, Priscilla Callahan-Lyon, Anne B. Chang, Andréanne Coté, Terrie Cowley, Paul Davenport, Satoru Ebihara, Ali A. El Solh, Patricio Escalante, Anthony Feinstein, Stephen K. Field, Dina Fisher, Cynthia T. French, Peter Gibson, Philip Gold, Anthony Harnden, Adam T. Hill, Richard S. Irwin, Peter J. Kahrilas, Karina A. Keogh, Kefang Lai, Kaiser Lim, J. Mark Madison, Mark A. Malesker, Stuart Mazzone, Alex Molassoitis, M. Hassan Murad, Mangala Narasimhan, Huong Q. Nguyen, Peter Newcombe, John J. Oppenheimer, Marcos I. Restrepo, Mark Rosen, Bruce Rubin, Jay H. Ryu, Jaclyn Smith, Susan M. Tarlo, Julie Turmel, Anne E. Vertigan, Gang Wang, Miles Weinberger, and Kelly Weir
Supplementary Data
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