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Unexplained Respiratory Disease Outbreak Working Group Activities — Worldwide, March 2007–September 2011

The Unexplained Respiratory Disease Outbreak (URDO) working group is a multidisciplinary team composed of approximately 40 scientists from across CDC with expertise in infectious and noninfectious respiratory diseases. The URDO working group was formed in 2004 to streamline CDC response efforts to assist local, state, and international public health officials in investigations of unexplained respiratory disease outbreaks. This report summarizes URDO working group activities from March 2007 through September 2011. During that period, the URDO working group was notified of 57 investigations and facilitated consultations with subject matter experts (in all 57 investigations), laboratory testing at CDC (in 42 investigations), and on-site field investigation support (in eight investigations). Of these 57 investigations, 41 occurred domestically, and 16 occurred internationally. An etiology was identified in 29 (51%) investigations; among these, the most commonly implicated pathogens were noninfluenza respiratory viruses (41%), influenza viruses (17%), Mycoplasma pneumoniae (14%), and Bordetella pertussis (14%). Notification occurred a median of 33 days after illness onset in the first case, which might have limited the ability to collect early laboratory specimens or epidemiologic data. Reducing delays in sample collection, epidemiologic investigations, and consultation with the URDO working group might increase the ability to identify etiologies and lead to more rapid control of these unexplained respiratory disease outbreaks.

The objectives of this analysis were to describe the investigations reported to the URDO working group from March 2007 through September 2011 and identify opportunities to improve the URDO working group's public health response. The URDO working group might be notified of unexplained respiratory disease outbreaks before the initiation of an investigation or during an ongoing investigation if uncertainty exists regarding the etiology or co-etiologies. Notifications were tracked beginning in March 2007, and correspondence from URDO working group investigators was collected. Because these materials often contained preliminary information from evolving investigations, this information was supplemented with field investigation final reports and publications, when available (1–6). Investigations were classified by the level of support provided, affected age group (children, adults, or both), setting, and whether the etiology was determined. Medians and ranges for the number of days from illness onset in the first case to notification were calculated, as were numbers of cases, hospitalizations, and deaths.

During March 2007–September 2011, the URDO working group was notified by state or international public health officials of 57 investigations. Of these, 41 occurred in the United States and its territories, and 16 occurred internationally (Figure). Notifications per year ranged from eight to 15 (Table 1). The median time from illness onset in the first case to notification (available for 37 investigations) was 33 days (range: 4–218 days). For all investigations, the URDO working group provided input through either telephone or e-mail consultation. Depending on the specific needs of the requestor, additional assistance ranged from advice given via conference calls with the working group (in 70% of investigations), to laboratory testing at CDC (74%), to on-site epidemiologic investigation assistance (14%) (Table 1). Once an etiology was identified or highly suspected, laboratory testing and investigation assistance were provided by CDC divisions with relevant subject matter expertise. Laboratory testing included molecular diagnostics for respiratory pathogens using polymerase chain reaction (PCR), serology, culture, histopathology, immunohistochemistry, and urine antigen testing. Additionally, in 13 investigations, the URDO working group provided laboratory support with TaqMan Array Cards (Life Technologies, Grand Island, New York), a PCR-based technology that tests simultaneously for approximately 20 respiratory pathogens (7).

Fifty-one investigations involved two or more cases. Of the other six investigations, one involved a pseudo-outbreak caused by clinical specimen contamination (4), and five involved single case consultations. The exact case count was available for 49 investigations; the median case number was 15 (range: one to 409 cases). The number of hospitalizations was available in 32 (56%) investigations (median: three; range: zero to 18). Among 26 (46%) investigations with two or more cases and numbers of cases and hospitalizations reported, the median percentage of cases resulting in hospitalization was 23% (range: zero to 100%). A total of 36 (63%) investigations had the number of deaths reported (median: zero, range: zero to 12, with one outlier from a wild-type poliovirus outbreak with 169 deaths reported) (3). The URDO working group was notified of this outbreak because it appeared initially to have a respiratory component. Age ranges of affected persons were reported in 52 (91%) investigations; adults were affected most commonly (Table 2). Communities (i.e., noninstitutional settings) and long-term–care facilities were the most common settings for outbreaks (Table 2).

The etiology was determined in 29 (51%) investigations, based on the interpretation of laboratory results with clinical and epidemiologic information. The most commonly identified etiologies were influenza viruses, Mycoplasma pneumoniae, Bordetella pertussis, and noninfluenza respiratory viruses (e.g., respiratory syncytial virus, adenovirus, and parainfluenza virus) (Table 2). Five (9%) investigations involved multiple etiologies. CDC provided laboratory support for 24 (83%) of 29 investigations with confirmed etiologies and for 18 (64%) of 28 that remained unexplained. Among 13 investigations involving TaqMan Array Cards, the etiology was identified for six (e.g., parainfluenza virus 3, Streptococcus pneumoniae, Chlamydophila pneumoniae, human parechovirus, human metapneumovirus, rhinovirus, and human enterovirus 68) (6). Of the seven investigations involving TaqMan Array Cards for which the etiology remained unclear, two or more pathogens were identified in five.

Reported by

Paul R. Cieslak, MD, Oregon Health Authority. April S. Britt, PharmD, Lauri Hicks, DO, Laura Conklin, MD, Chris Van Beneden, MD, Laurel E. Garrison, MPH, Jonas Winchell, PhD, Respiratory Diseases Br, Div of Bacterial Diseases; Eileen Schneider, MD, Dean Erdman, DrPH, Div of Viral Diseases; Alicia Fry, MD, Seema Jain, MD, Tim Uyeki, MD, Lyn Finelli, DrPH, Steve Lindstrom, PhD, Influenza Div; Thomas A. Clark, MD, Maria-Lucia Tondella, PhD, Meningitis and Vaccine Preventable Diseases Br, Div of Bacterial Diseases, National Center for Immunizations and Respiratory Diseases; Wun-Ju Shieh, MD, Sherif Zaki, MD, PhD, Div of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, for the Unexplained Respiratory Disease Outbreak Working Group; Katherine E. Fleming-Dutra, MD, EIS Officer, CDC. Corresponding contributor: Katherine E. Fleming-Dutra, ftu2@cdc.gov, 404-639-4243.

Editorial Note

Respiratory disease outbreak investigations present several challenges. Clinical presentation alone usually is insufficiently distinct to permit identification of an etiology. Respiratory specimens of good quality can be difficult to obtain in a timely manner, and local laboratory capability to test for multiple potential causes often is limited. Furthermore, rapid identification of the etiology is important for timely implementation of control measures (e.g., appropriate infection control, vaccination, and chemoprophylaxis). To enhance public health responses to unexplained respiratory outbreaks, CDC integrated epidemiologic and laboratory expertise from across the agency to form the URDO working group to advise, conduct laboratory testing, and facilitate CDC assistance for these outbreaks. During the evaluation period (March 2007–September 2011), the URDO working group was notified of 57 investigations, 29 (51%) of which resulted in the identification of the etiology. Common respiratory pathogens, such as influenza viruses, Mycoplasma pneumoniae, Bordetella pertussis, and noninfluenza respiratory viruses, were identified as the etiology for several outbreaks. Additionally, the URDO working group assisted with investigations of illnesses with respiratory symptoms that were determined to be primarily nonrespiratory (e.g., Rickettsia rickettsii infection and polio). The URDO working group has capacity to provide rapid, multipathogen testing with TaqMan Array Cards for investigations in which several etiologies are under consideration.

Information is available to guide investigations of unexplained respiratory disease outbreaks. These materials include documents that can assist public health officials with establishing case definitions, forming line lists, and generating epidemic curves, as well as a sample respiratory illness questionnaire and instructions for specimen collection (8). Of particular importance are disease outbreaks that 1) might be interrupted by timely vaccination (5), environmental interventions, or other control methods; 2) occur in institutional settings or among vulnerable populations; 3) might involve bioterrorism agents; 4) are severe, large, or rapidly progressive; or 5) cause public concern (8,9). Such outbreaks might warrant notification of the URDO working group and further investigation.

The findings in this report are subject to at least three limitations. First, the fraction of unexplained respiratory outbreaks that are reported is not known; reported outbreaks might not represent the distribution of etiologies among all unexplained respiratory outbreaks. Second, the URDO working group is provided information while investigations are under way but does not systematically collect final reports from local public health officials. Therefore, the data in this report likely underestimate case counts, hospitalizations, and deaths. Finally, information was not collected about unexplained respiratory disease investigations occurring before March 2007, so determining whether the URDO working group has improved identification of etiologies or outbreak mitigation is not possible.

An etiology was identified in only about half of all investigations by the URDO working group. This might result, in part, from delays in clinical specimen collection because many pathogens (e.g., influenza) only can be detected for a short time after illness onset (10). The URDO working group was notified of each outbreak a median of 33 days after illness onset in the first case. These delays might have resulted from delayed outbreak recognition or because local investigators waited until local testing failed to identify the etiology. Reducing the time between outbreak recognition and notification might increase the likelihood that optimal respiratory specimens are collected. However, even when timely specimens are obtained, sensitive and specific laboratory diagnostic tests might not be available locally or at CDC for some known pathogens and for new pathogens. Finally, gaps in available clinical and epidemiologic information might decrease the URDO working group's ability to determine plausible etiologies and to recommend appropriate diagnostics.

Health-care providers and facilities are encouraged to report suspected outbreaks early to local public health officials, and health officials are invited to consult the URDO working group early in the course of any unexplained respiratory disease investigation. Additionally, CDC recommends that public health officials collect and store clinical specimens as an investigation evolves for potential future testing. The URDO working group provides an example of a successful, interdisciplinary approach to providing assistance to public health professionals in the United States and abroad. The URDO working group can be contacted through CDC's Emergency Operations Center by telephone, at 770-488-7100. Additional information and resources are available at http://emergency.cdc.gov/urdo.

Acknowledgments

Members of the URDO working group: Sasha Klimov, Mike Jhung, Ashley Fowlkes, Greg Armstrong, Larry Anderson, David Shay, Gayle Fischer Langley, Nicole Alexander, Barry Fields, Marc Fischer.

References

  1. CDC. Outbreak of adenovirus 14 respiratory illness—Prince of Wales Island, Alaska, 2008. MMWR 2010;59:6–10.
  2. Esposito D, Gardner T, Schneider E, et al. Outbreak of pneumonia associated with emergent human adenovirus serotype 14—southeast Alaska, 2008. J Infect Dis 2010;202:214–22.
  3. Grard G, Drexler JF, Lekana-Douki S, et al. Type 1 wild poliovirus and putative enterovirus 109 in an outbreak of acute flaccid paralysis in Congo, October–November 2010. Euro Surveill 2010;15(47).
  4. Mandal S, Tatti KM, Woods-Stout D, et al. Pertussis pseudo outbreak linked to specimens contaminated by Bordetella pertussis DNA from clinic surfaces. Pediatrics 2012;129:e424–30.
  5. Wei SC, Tatti K, Cushing K, et al. Effectiveness of adolescent and adult tetanus, reduced-dose diphtheria, and acellular pertussis vaccine against pertussis. Clin Infect Dis 2010;51:315–21.
  6. Jacobson LM, Redd JT, Schneider E, et al. Outbreak of lower respiratory tract illness associated with human enterovirus 68 among American Indian children. Pediatr Infect Dis J 2012;31:309–12.
  7. Kodani M, Yang G, Conklin L, et al. Application of TaqMan low-density arrays for simultaneous detection of multiple respiratory pathogens. J Clin Microbiol 2011;49:2175–82.
  8. CDC. How to investigate unexplained respiratory disease outbreaks (URDO). Atlanta, GA: US Department of Health and Human Services, CDC; 2011. Available at http://emergency.cdc.gov/urdo. Accessed June 25, 2012.
  9. Reingold AL. Outbreak investigations—a perspective. Emerg Infect Dis 1998;4:21–7.
  10. Carrat F, Vergu E, Ferguson NM, et al. Time lines of infection and disease in human influenza: a review of volunteer challenge studies. Am J Epidemiol 2008;167:775–85.

What is already known on this topic?

Respiratory disease outbreaks can present investigation challenges, especially because of the many potential etiologies with overlapping clinical presentations.

What is added by this report?

The Unexplained Respiratory Disease Outbreak (URDO) working group provided varying forms of support, ranging from telephone consultation to laboratory testing to on-site field investigation assistance for 57 domestic and international investigations during March 2007–September 2011. A cause was found for 51% of the outbreaks investigated. The most common causes were influenza viruses, Mycoplasma pneumoniae, Bordetella pertussis, and noninfluenza respiratory viruses.

What are the implications for public health practice?

Reducing delays in sample collection, epidemiologic investigations, and consultation with the URDO working group might increase the ability to identify etiologies and lead to more rapid control of these unexplained respiratory disease outbreaks.


FIGURE. Number of notifications received by the Unexplained Respiratory Disease Outbreak working group, by state/territory — United States, March 2007–September 2011*

The figure shows the number of notifications received by the Unexplained Respiratory Disease Outbreak working group, by state/territory in the United States, during March 2007-September 2011. During March 2007-September 2011, the work¬ing group was notified by state or international public health officials of 57 investigations. Of these, 41 occurred in the United States and its territories, and 16 occurred internation¬ally.

Abbreviations: PR = Puerto Rico; USVI = U.S. Virgin Islands.

* International notifications: Mexico (four) and one each for Australia, Brazil, Guatemala, Honduras, Kenya, Nepal, Nicaragua, Panama, Republic of Congo, Rwanda, Taiwan, and United Kingdom.

Alternate Text: The figure above shows the number of notifications received by the Unexplained Respiratory Disease Outbreak working group, by state/territory in the United States, during March 2007-September 2011. During March 2007-September 2011, the work¬ing group was notified by state or international public health officials of 57 investigations. Of these, 41 occurred in the United States and its territories, and 16 occurred internation¬ally.


TABLE 1. Number and percentage of notifications received by the Unexplained Respiratory Disease Outbreak working group, by year and type of support provided — worldwide, March 2007–September 2011

Notifications/Type of support

2007*

2008

2009

2010

2011*

Total

No.

(%)

No.

(%)

No.

(%)

No.

(%)

No.

(%)

No.

(%)

Total no. of notifications

8

(100)

14

(100)

15

(100)

9

(100)

11

(100)

57

(100)

Epidemiologic consultation via conference call

6

(75)

11

(79)

9

(60)

7

(78)

7

(64)

40

(70)

Laboratory testing§

6

(75)

13

(93)

9

(60)

8

(89)

6

(55)

42

(74)

Field epidemiologic investigation§

4

(50)

1

(7)

1

(7)

1

(11)

1

(9)

8

(14)

* Not full years (i.e., March–December for 2007 and January–September for 2011).

All outbreak notifications resulted in at least a telephone or e-mail consultation.

§ Laboratory testing and field epidemiologic investigation support was provided by CDC teams from divisions with subject matter expertise in the identified or suspected etiologies.


TABLE 2. Number (N = 57) and percentage of notifications received by the Unexplained Respiratory Disease Outbreak (URDO) working group, by selected characteristics — worldwide, March 2007–September 2011

Characteristic

Notifications*

No.

(%)

Information on age of affected persons available

52

(91)

Principal age group affected

Children

12

(23)

Adults

30

(58)

Children and adults

10

(19)

Information on setting available

51

(89)

Community

21

(41)

Long-term–care facility

10

(20)

School/Child care facility/College

5

(10)

During travel

8

(16)

Prison

3

(6)

Acute-care facility§

2

(4)

Other

2

(4)

Consultation for nonoutbreak situations

6

(11)

Consultation on single severe case**

5

(83)

Pseudo-outbreak††

1

(17)

No. of investigations with etiologies determined

29

(51)

Multiple pathogens identified

5

(17)

Specific etiologies identified§§

Influenza viruses¶¶

5

(17)

Mycoplasma pneumoniae

4

(14)

Bordetella pertussis

4

(14)

Streptococcus pneumoniae

2

(7)

Noninfluenza respiratory viruses***

12

(41)

Other†††

7

(24)

* Numbers as reported to the URDO working group; final outbreak case report numbers included only if provided to the URDO working group.

Includes investigations that occurred in noninstitutional settings.

§ Hospital (one notification) and psychiatric treatment facility (one).

Refugee camp (one notification) and workplace (one).

** Case of severe community-acquired pneumonia (one notification); cases of severe respiratory disease in single travelers (four).

†† Determined to be caused by contamination of clinical specimens and not a disease outbreak.

§§ Includes investigations with multiple pathogens identified.

¶¶ Influenza A (H1N1)pdm09 (four notifications) and influenza A (H3N2) (one).

*** Respiratory syncytial virus (three notifications), parainfluenza virus 3 (two), adenovirus (two), adenovirus 14 (one), and one each for human metapneumovirus, parechovirus, enterovirus 68, and rhinovirus.

††† One notification each for Chlamydophila pneumonia, human herpesvirus 2, Legionella, Bordetella parapertussis, Bordetella pertussis pseudo-outbreak, Rickettsia rickettsii, and wild poliovirus type 1.


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