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Pulmonary Infections
Moderators: Dr. Dani Zander, Dr. David Hwang and Dr. Osamu Matsubara
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Section 2 -
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Diagnosis of Emerging Pulmonary Infections

Sherif R. Zaki
Chief, Infectious Disease Pathology Activity
National Center for Infectious Diseases
Centers for Disease Control and Prevention
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Contrary to predictions made in the later half of the 20th century, infectious diseases remain the
leading cause of death worldwide. Infectious disease pathologists have a longstanding history of
contributing to the diagnosis and identification of infectious disease agents. Pathologists are
characteristically among the first health care workers involved in recognizing infectious disease
outbreaks and hence are in an excellent position to discover new zoonotic diseases and other emerging
infectious disease syndromes.

Pulmonary infections in man are caused by a variety of organisms including viruses, bacteria, fungi,
rickettsia, parasites and other microbes. Lung may also be involved as part of systemic infection as
seen for example with parvoviridae and viral hemorrhagic fevers. The diagnosis of pneumonia, suspected
by history and clinical manifestations, also can be supported histopathologically, and the overall
pattern of histopathologic lesions may suggest a specific diagnosis. In addition to histologic pattern
recognition, immunohistochemistry (IHC), and in situ hybridization (ISH) in tissue, several other
diagnostic tests are available to aid the pathologist in microbial identification. Cell culture
techniques, serology, polymerase chain reaction (PCR), and electron microscopy (EM) all play vital roles
in the diagnosis of these infections. These powerful techniques continue to provide excellent tools for
the pathologist in addressing pathogenesis research, consultation cases, and moreover, the recent
challenges posed by new, emerging, and reemerging diseases.
Table 1. Recent Outbreaks of Emerging Pulmonary Infections
| Year | Pathogen | References |
| 93 | Hantavirus | 1-3 |
| 95 | Leptospirosis | 20-22 |
| 97 | H5N1 Avian Influenza | 17 |
| 99 | Nipah virus | 18 |
| 01 | Anthrax | 19 |
| 03 | SARS | 4-13 |
| 03-04 | Influenza (including pediatric deaths and avian influenza) | 14-16 |

The presentation will provide an overview of the common pathologic findings present in pneumonias and
other pulmonary infections along with discussion of current diagnostic testing modalities to detect
pulmonary pathogens. Outbreaks of emerging and re-emerging pulmonary diseases that CDC investigated
during recent years including hantavirus, sudden acute respiratory syndrome (SARS), leptospirosis,
anthrax, and influenza (including avian influenza) will also be presented. The differential diagnosis of
these entities as well as systematic and syndromic pathologic approaches to achieve an etiologic
diagnosis will also be discussed.

References
Bunyaviridae
- Nolte KB, Feddersen RM, Foucar K, Zaki SR, Koster FT, Madar D, Merlin TL, McFeeley PJ, Zumwalt RE. Hantavirus pulmonary syndrome in the United States: a pathological description of a disease caused by a new agent. Human Pathology 1995;26:110-20.

- Zaki SR, Albers RC, Greer PW, Coffield LM, Armstrong LR, Khan AS, Khabbaz R, Peters CJ. Retrospective diagnosis of a 1983 case of fatal hantavirus pulmonary syndrome. Lancet 1994;343:1037-38.

- Zaki SR, Greer PW, Coffield LM, Goldsmith CS, Nolte KB, Foucar K, Feddersen RM, Zumwalt RE, Miller GL, Khan AS, Rollin PE, Ksiazek TG, Nichol ST, Mahy BWJ, Peters CJ. Hantavirus pulmonary syndrome: Pathogenesis of an emerging infectious disease. American Journal of Pathology 1995;146:552-79.
Coronaviridae
- Chong PY, Chui P, Ling AE, Franks TJ, Tai DY, Leo YS, Kaw GJ, Wansaicheong G, Chan KP, Ean Oon LL, Teo ES, Tan KB, Nakajima N, Sata T, Travis WD. Analysis of deaths during the severe acute respiratory syndrome (SARS) epidemic in Singapore: challenges in determining a SARS diagnosis. Arch Pathol Lab Med 2004;128(2):195-204.

- Ding Y, Wang H, Shen H, Li Z, Geng J, Han H, Cai J, Li X, Kang W, Weng D, Lu Y, Wu D, He L, Yao K. The clinical pathology of severe acute respiratory syndrome (SARS): a report from China. J Pathol. 2003;200(3):282-9.

- Franks TJ, Chong PY, Chui P, Galvin JR, Lourens RM, Reid AH, Selbs E, McEvoy CP, Hayden CD, Fukuoka J, Taubenberger JK, Travis WD. Lung pathology of severe acute respiratory syndrome (SARS): a study of 8 autopsy cases from Singapore. Human Pathology 2003;34(8):743-8.

- Goldsmith CS, Tatti KM, Ksiazek TG, Rollin PE, Comer JA, Lee WW, Rota PA, Bankamp B, Bellini WJ, and Zaki SR. Ultrastructural characterization of Severe Acute Respiratory Syndrome (SARS) Coronavirus. EID 2004;10(2):320-26.

- Ksiazek TG, Erdman D, Goldsmith CS, Zaki SR, Peret T, Emery S, Tong S, Urbani C, Comer JA, Lim W, Rollin PE, Dowell SF, Ling AE, Humphrey CD, Shieh WJ, Guarner J, Paddock CD, Rota P, Fields B, DeRisi J, Yang JY, Cox N, Hughes JM, LeDuc JW, Bellini WJ, Anderson LJ. A novel coronavirus associated with Severe Acute Respiratory Syndrome. N Engl J Med 2003;348(20):1953-66.

- Nicholls JM, Poon LL, Lee KC, Ng WF, Lai ST, Leung CY, Chu CM, Hui PK, Mak KL, Lim W, Yan KW, Chan KH, Tsang NC, Guan Y, Yuen KY, Peiris JS. Lung pathology of fatal severe acute respiratory syndrome. Lancet 2003;361(9371):1773-8.

- Roberts A, Vogel L, Guarner J, Hayes N, Murphy B, Zaki S, Subbarao K. Severe acute respiratory syndrome coronavirus infection of golden Syrian hamsters. J Virol 2005; 79(1):503-11.

- Subbarao K, McAuliffe J, Vogel L, Fahle G, Fischer S, Tatti K, Packard M, Shieh WJ, Zaki S, Murphy B. Prior infection and passive transfer of neutralizing antibody prevent replication of severe acute respiratory syndrome coronavirus in the respiratory tract of mice. J Virol, 2004;78(7):3572-7.

- Shieh W-J, Hsiao C-H, Paddock CD, Guarner J, Goldsmith CS, Tatti K, Packard M, Mueller L, Wub M-Z, Rollin P, Su I-J, Zaki SR. Immunohistochemical, in situ hybridization, and ultrastructural localization of SARS-associated coronavirus in lung of a fatal case of severe acute respiratory syndrome in Taiwan. Hum Pathol 2005; 36, 303–9.

- Zaki, SR, Goldsmith CS. SARS Coronavirus Infection: Pathology and pathogenesis of an emerging virus disease. In: Birkhäuser Advances in Infectious Diseases Schmidt, Axel; Wolff, Manfred H.; Weber, Olaf (Eds.). Basel, Switerzerland 2005; 87-99.
Orthomyxoviridae
- Yeldandi AV, Colby TV. Pathologic features of lung biopsy specimens from influenza pneumonia cases. Hum Pathol.1994;25:47-53.

- Guarner J, Shieh WJ, Dawson J, Subbarao K, Shaw M, Ferebee T, Morken T, Nolte KB, Freifeld A, Cox N, Zaki SR. Immunohistochemical and in situ hybridization studies of influenza A virus infection in human lungs. American Journal of Clinical Pathology 2000;114:227-33.

- Update: Influenza-Associated Deaths Reported Among Children Aged <18 Years - United States, 2003-04 Influenza Season. MMWR Morbidity and Mortality Weekly Report 2004;52(Dispatch):1-2;1254-55.

- Ungchusak K, Auewarakul P, Dowell SF, Kitphati R, Auwanit W, Puthavathana P, Uiprasertkul M, Boonnak K, Pittayawonganon C, Cox NJ, Zaki SR, Thawatsupha P, Chittaganpitch M, Khontong R, Simmerman JM, Chunsutthiwat S. Probable person-to-person transmission of Avian Influenza A (H5N1). N Engl J Med 2005;352(4):333-40.
Paramyxoviridae
- Wong, KT, Shieh WJ, Kumar S, Norain K, Abdullah W, Guarner J, Goldsmith CS, Chua KB, Lam SK, Tan CT, Goh KJ, Chong HT, Jusoh R, Rollin PE, Ksiazek TG, Zaki SR, and the Nipah Virus Pathology Working Group. Nipah virus infection: pathology and pathogenesis of an emerging paramyxoviral zoonosis. American Journal of Pathology 2002;161(6):2153-67.
Bacillus anthracis
- Guarner J, Jernigan JA, Shieh W-J, Tatti K, Flannagan LM, Stephens DS, Popovic T, Ashford D, Perkins BA, Zaki SR and Anthrax Pathology Working Group. Pathology and pathogenesis of bioterrorism-related inhalational anthrax. American Journal of Pathology, 2003;163(2):701-9.
Leptospira sp.
- Zaki SR, Shieh W-J, and the Epidemic Working Group. Leptospirosis associated with an outbreak of acute febrile illness and pulmonary hemorrhage, Nicaragua 1995. Lancet, 1996;347:535-36.

- Trevejo RT, Rigau-Perez JG, Ashford DA, McClure EM, Jarquin-Gonzalez C, Amador JJ, De Los Reyes JO, Gonzalez A, Zaki SR, Shieh W-J, McLean RG, Nasci RS, Weyant RS, Bolin CA, Bragg SL, Perkin BA, Spiegel RA. Epidemic leptospirosis associated with pulmonary hemorrhage--Nicaragua, 1995. Journal of Infectious Diseases, 1998;178:1457-63.

- Shieh, W-J, Edwards C, Spiegel RA, Zaki SR. Spirochetal infections: Leptospirosis. In: Tropical Infectious Diseases. Eds. Guerrant RL, Krogstad DJ, Maguire JA, Walker DH, Weller PF Churchill Livingstone, Inc., New York, New York, 1999;49:547-555.
General
- Zaki SR, Paddock C. The emerging role of pathology in infectious diseases. In: Emerging Infections III: Eds. Scheld WM, Craig WA, Hughes JM; American Society for Microbiology, Washington DC, ASM Press, 1999;3:181-200.
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