Atypical pneumonia refers to pneumonia caused by certain atypical pathogens rather than typical bacteria. In the 1930s, pneumonia cases emerged that were clinically distinct from bacterial pneumonia. Over decades, research identified the pathogens responsible as Chlamydia, Legionella, and Mycoplasma species. Through the 1930s-1960s, scientists like Eaton, Liu, and Chanock used techniques like cold agglutination testing, animal inoculation and staining to determine that Mycoplasma pneumoniae was the causative agent of the majority of atypical pneumonia cases, which they named the Eaton agent. This resolved the nature of the atypical pneumonia-causing organism.

1. ATYPICAL PNEUMONIA
A series

2. Pneumonia
An inflammatory
condition of the lung -
especially affecting the
microscopic air sacs (alveoli)
associated with
•fever,
•chest symptoms, and
•lack of air space (consolidation) on a chest X-ray
Fishman’s Pulmonary Diseases and Disorders, vol 2, 3rd edn, McGraw Hill, 1996

3. What is atypical pneumonia ?
• In 1930’s , the term ‘atypical pneumonia’ was first applied
to viral community-acquired pneumonias (CAP) that were
clinically and radiologically distinct from bacterial CAPs
• Over the past decades, atypical pneumonia has come to
mean lower respiratory tract infections due to specific
respiratory pathogens
Chlamydia psittaci (psittacosis)
Francisella tularensis (tularemia)
Coxiella burnetii (Q fever)
Chlamydia pneumoniae
Mycoplasma pneumoniae or
Legionella species
Fishman’s Pulmonary Diseases and Disorders, vol 2, 3rd edn, McGraw Hill, 1996

4. (Typical)Pneumonia Atypical Pneumonia
• Typical CAPs with clinical and • Systemic infectious disease
laboratory findings limited to with a pulmonary component
the lungs
• Typical bacterial pathogens • In contrast, most of the
have classically responded to atypical pathogens do not
b-lactam antimicrobial therapy have a bacterial cell wall and
some are
because they have a cell wall intracellular, e.g., Legionella, a
amenable to b-lactam nd still others are
disruption. paracellular, e.g., M.
• Chest radiograph will show pneumoniae
lobar or segmental • This finding can also be seen in
homogeneous opacity in over nearly half the cases of
80% of typical bacterial atypical infection, but diffuse
pneumonias. patchy or ground glass
shadows are more commonly
observed.
*Fishman’s Pulmonary Diseases and Disorders, vol 2, 3rd edn, McGraw Hill, 1996
*The atypical pneumonias: clinical diagnosis and importance,B.A.Cunha,Clin Microbiol Infect 2006; 12 (Suppl. 3): 12–24

5. Clinical
pneumonia
No extrapulmonary features Extrapulmonary features
(loose stools,abdominal
(typical bacterial pneumonia) pain,meningism,facial rash)
Streptococcus
pneumoniae No zoonotic contact history Zoonotic contact history
Haemophilus influenzae Mycoplasma, Psittacosis,
Chlamydia (no RB), Q fever (RB+) ,
Group A streptococci
Legionnaires’ disease(RB +) Tularemia (no RB)
Klebsiella pneumoniae,etc.
RB : Relative Bradycardia, + : present
The atypical pneumonias: clinical diagnosis and importance,B.A.Cunha,Clin Microbiol Infect 2006; 12 (Suppl. 3): 12–24
J Infect. 1996 Nov;33(3):185-91.Relative bradycardia in infectious diseases.Ostergaard L, Huniche B, Andersen PL

6. • Atypical CAPs represent approximately 15% of
all CAPs.
• From India, atypical organisms have rarely
been isolated from patients with CAP, mainly
due to lack of facilities for culture/serology of
these organisms.
ǂ Porath A, Schaeffer F, Lieberman D. The epidemiology of community acquired pneumonia among
hospitalized adults. J Infect 1997 ; 34 : 41 - 48.

7. 1930 to 1963

8. • Nonfiltrable viruses,1938
• Serum used to infect animals, 1942
• No growth on standard medium or agar
• 1943,Peterson and colleagues - suggested the
use of the cold agglutination study as a
diagnostic test.
Filterable virus
A virus particle small enough to pass through a filter of diatomaceous earth or porcelain, which will
not pass bacteria:chiefly historical or an informal indicator of size.

9. • Meiklejohn and Eaton, serum samples of the
patients who had symptoms of primary atypical
pneumonia. compared them with serum from
patients with other respiratory diseases
• Goal : determine how frequently cold agglutinin
titers were found in primary atypical pneumonia
in comparison with other respiratory diseases.
• Serum tested for cold agglutinins
– at the onset of disease,
– throughout the course of disease, and
– during convalescence
Cold Agglutination test
The serial dilutions of patients serum are mixed with an equal volume of 0.2% washed human O group
erythrocytes at low temperature.The clumping is observed at 4°C overnight.
However the clumping is dissociated at 37°c.
A titer of 1:32 or > is suggestive.

10. Serum samples
for Cold
agglutinins
Test Control
82 % 18 % All
(titer > 1:20) (titer ≤1:20) (titer≤1:20)
Meiklejohn G. The cold agglutination test in the diagnosis of primary atypical pneumonia. Proc Soc Exp Biol Med
1943;53:181,193 EOA.

11. Levels of Cold agglutinins and transmissibility
5 Cold agglutinin titer
4.5 Transmissibility
4 Peak at 12 to 25 days
3.5
3
2.5
2
1.5
1
0.5
0
Convalescent phase
(2 months or more)

12. • Confounding factor : storage of samples
• Despite that fact , this was the first time that a
specific test was identified as directly aiding in
the diagnosis of this clinical syndrome.
• Meiklejohn himself said that this was a
“ROUNDABOUT WAY“ of testing for the
disease.
Roundabout way - one that is used temporarily while a main route is blocked

13. Eaton :
• Laboratories were unable to culture it using
their standard techniques.
• Began experiments injecting serum of
infected individuals into cotton rats to further study
the agent
• ‘‘The exact nature of the agent causing primary
atypical pneumonia has not been established
but filtration data indicate that it may be
representative of a class of agents sensitive to
aureomycin but somewhat smaller than viruses
of the psittacosis-lymphogranuloma group which
are also inhibited by this drug.’’
As a result of his efforts to isolate and identify the organism,
it is given the name ‘‘Eaton agent”

14. • 1954 : Watson developed Indirect Fluorescent
Antibody(IFA) test for the Eaton agent.
• 1957 : Liu tested original and new samples.(Liu
antibody test)
• Revealed that among cases of clinically diagnosed
primary atypical pneumonia with positive cold
agglutinin titers, IFA test was posotive in 67-90%
patients.
• Confirming Eaton agent as the causative
organism.

15. By 1960, Cook and colleagues
• Prove the link between cold agglutinin and the
Liu antibody test.
• Inoculate cotton rats intranasally with isolates
from these samples
• The serum samples that were obtained from
these atypical pneumonia patients were retested
and found that most had either a positive cold
agglutinin test or a positive streptococcus MG
test, while in control group both these tests were
negative.
All the efforts of Cook and colleagues was directed towards proving Eaton agent
as the cause of this atypical pneumonia syndrome
Streptococcus MG test :
The test is performed by mixing serial dilutions of patients serum with heat killed suspension of
Streptococcus MG. The sample is incubated at 37°c.
The agglutination titer of 1:20 or > is suggestive.

16. Cook and colleagues
• Inoculated all strains available to them in chick embryos and
subsequently into an animal model.
• Cold agglutinin,streptococcus MG test and indirect
fluorescent antibody test to confirm the presence of Eaton
agent.
• Analyzed lung tissue from the infected animals.
• Performed complement fixation studies on their
samples, searching for
– Q fever,
– psittacosis,
– lymphogranuloma venereum,
– adenovirus,
– coxsackie B, and
– respiratory syncytial virus
• Performed hemaglutination inhibition study on all samples

17. Inferences from the work of Cook and
colleagues
• Indirect antibody testing for Eaton agent had a
relatively high specificity for primary atypical
pneumonia.
• The disease principally affects younger
individuals, and rather than occurring in large
outbreaks, could occur sporadically at any
time of the year.
• Excluded other differential diagnoses

18. • 1960, Chanock and colleagues studied atypical
pneumonia in children using the same
technique as Cook and colleagues.Study
showed that the indirect antibody test may
have been even more specific than the adult
study had proven.

19. In 1961, Chanock and colleagues
• studied a population of 238 Marine Corps with
atypical pneumonia
• All demonstrated an elevated cold agglutinin titer
•

20. • Eaton and Liu had never confirmed their thoughts on
the precise nature of the organism
• 1963, Goodburn and his associates had been
experimenting with
– Giemsa staining
– Tissue cultures
– Chick embryos (which had been the only method of growing the
organism)
for evidence of Eaton agent.
• Finally able to visualize coccobacillary bodies on
staining.

21. • Owing to the
– Organism’s size,
– Clinical manifestations,
– Giemsa staining evidence, and
– Sensitivity of the organism to antibiotics and some organic
gold compounds,
they felt that rather than being a virus, it
was a pleuropneumonia-like organism (PPLO) of
the mycoplasma group.

22. Chanock RM, 1963
Tissue Special Difco reclassified as
Eaton agent cultures from PPLO media Mycoplasma
chick embryos and agar pneumoniae
Eaton and Chanock confirmed
the Mycoplasma genus once the
organism could be cultured on a
special media. Also found,unless
media contained serum or egg
yolk, no organismal growth
could be seen
Science,1963 May 10;140(3567):662,
Mycoplasma pneumoniae: proposed nomenclature for atypical pneumonia organism (Eaton agent).
CHANOCK RM

23. Eaton, (1930-1963)
Liu, (1930-1950)
Cook and colleagues, (1960)
Goodburn and associates , (1963)
Chanock RM, (1963)

25. Thank
you
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