cytokines and pleyral diseases

1. Cytokines in lung and
pleural diseases
Dr. Sushant Kumar Nanda
1st yr DM Resident
SCB MCH, Cuttack

2. WHAT IS A CYTOKINE?
• Cytokines are soluble peptides secreted by cells
that affect the behavior of either the same or
nearby cells through nonenzymatic means.
• Often they are glycopeptides and typically exert
their effects at very low concentrations in the
picomolar to nanomolar range.
• Within this broad class are a number of subclasses,
including polypeptide growth factors,
interleukins(ILs) ,interferons and colony-stimulating
factors.

3. Cytokines and the lung
• The role that cytokines play in the regulation and modulation of
immunological and inflammatory processes is striking.
• The lung is particularly dependent on tightly regulated immunological
and inflammatory processes since it is exposed to a large and varied
burden of infectious agents as well as a diverse group of noxious
gases and particulates
• The lung defends itself from these injurious agents by deploying
cytokine-regulated host defence mechanisms wherever it interfaces
with the external environment
Cytokines and the lung. G.B. Toews. #ERS Journals Ltd 2001.

4. General inflammatory
response in airways disease

6. • 3 distinct cytokine profiles in the sputum in AE-COPD cases,
namely Th1high-Th17high, Th1low-Th17low and Th1high-Th17
low patterns, which exhibited significantly different clinical
outcomes.
• Th1/Th17 imbalance is associated with the severity of COPD.
• Sufficient Th17 cytokine responses (production of IL-17A and IL-
22, especially IL-17A) can reduce the frequency and severity of
the exacerbation.
• The Th1/Th17 balance may be a specific target for therapeutic
manipulation of COPD.

7. Anti-cytokine therapies in severe asthma

8. TB & the host immune response
• The protective immune response to M. tuberculosis is
predominately T-cell dependant and relies heavily upon the
production of Th1 cytokines.
• However, it appears that in TB patients the Th1 cytokines are
produced at high levels at the site of infection, although their
systemic levels may be reduced. By contrast, the systemic Th2
cytokine levels appear to be increased.
• While Th1 cytokines e.g. IFN-gamma, IL-2 and IL-12, promote
cell-mediated immunity, which is essential for the control of
mycobacterial infection, the Th2 cytokines IL-4 and IL-5, as well
as the regulatory cytokine IL-10, may inhibit the protective Th1-
mediated response.

9. Rational and therapeutic potential
of cytokines in TB
• A limited number of clinical trials and case studies have been
conducted to determine the therapeutic effect of Th1 cytokines in TB
patients. In the majority of these studies, cytokine therapy was
administered to patients with multidrug-resistant TB. The overall
outcome is that the adjunct cytokine treatment holds some promise
but that no definitive breakthrough has been made for any of the
cytokines. At present, IFN-g appears to have the greatest promise for
potential future use in clinical practice.

10. Cytokine therapy of nontuberculous
mycobacterial infections
• a randomized, double-blind, placebo-controlled clinical trial was carried
out to evaluate the effect of IFN-γ as an immunoadjuvant to
chemotherapy in patients with atypical mycobacterial lung disease
caused by M. avium.
• Patients received placebo (n = 14) or recombinant human IFN-gamma (n
= 18) daily for 1 month and then three-times per week for up to 6
months as adjuvant to daily chemotherapy.
• At the end of treatment, 72% of the patients treated with IFN-γ
were evaluated as complete responders compared with only 36% in the
placebo group, with a significantly earlier improvement in respiratory
symptoms, fewer pulmonary lesions and a significant reduction in
disease-related deaths.
• These data suggest that IFN-gamma; is useful and well tolerated as
adjuvant therapy in patients with pulmonary atypical mycobacteriosis

11. Conclusion:
• COPD related to tobacco use is more severe than the post-TB form.
• The pathogenesis of COPD in patients with a history of smoking involves several
cytokines in the local pathway such as IL-1α, IL-1β, IL-6, IL-17, TNF-α, IL-8, MIP-1β
and VEGF.
• In contrast the pathogenesis of the post-TB form seems to imply fewer
inflammatory markers with IL-1RA, IL-1β, GRO and sCD40L as local marker.

12. • Clara Cell Protein 16 (CC16), also known as uteroglobin, is the major protein
secreted by Clara cells and the most abundant protein in bronchoalveolar
lavage fluid (BALF).
• However, the regulation and functions of CC16 during G- bacterial infection are
unknown.
• This study assessed the regulation of CC16 in response to Klebsiella
pneumoniae (K. pneu) and to investigate the role of CC16 in bronchial epithelial

13. K. Pneumoniae infection reduces CC16 expression in bronchial epithelial
cells. The decreased CC16 level promotes K. pneu-induced
inflammation, ROS, and apoptosis. Moreover intracellular rather than
extracellular CC16 has an anti-inflammatory effect in bronchial epithelial
cells

14. • Accumulating evidence point to a cytokine driven
inflammatory process as a major contributor to the
development of pulmonary hypertension.
• Cytokines have emerged not only as major contributing
factors in the pathogenesis of pulmonary hypertension but
also might act as biomarkers both for diagnosis and clinical
outcome of patients with PH.

15. • Elevated serum levels of IL-1beta were found in PAH patients
and correlate with a worse outcome.
• IL-18 is elevated in the patients with PAH and there is evidence
that abnormal levels play a role in vasculopathy of the
pulmonary circulation.
• IL-6 might be one of the most important cytokines involved in
the pathogenesis of PAH and hypoxia-induced PH.
• Serum levels are significantly higher in patients as compared
with normal controls and correlate with patients survival and
levels of IL-6 also turned out to be a better predictor for survival
than traditional clinical tests.
• IL-6 seems to have a strong impact on the development of
pulmonary hypertension in COPD

16. • Elevated serum levels of IL-8 were found in PAH
patients and were also described as predictor of
survival in PAH patients.
• IL-8 is thought to play an important role in the
development of PAH, especially in early phases of
vascular remodeling.
• Patients with PAH in association with connective
tissue diseases show higher IL-8 serum levels than
patients without PAH
• Patients under a Ph target therapy with prostacyclin
agonists showed higher levels of IL-10 compared to
patients without such therapy.
• Conversely, PAH patients showed a significant
decrease in IL-10 expression following
cardiopulmonary bypass operation

17. • IL-13 promotes vascular remodeling in pulmonary
hypertension. It is too early to make conclusions on the
potential use of IL-13
• Elevated serum levels of TNF-α were described in PAH
patients. There is an increase in concentrations of TNF-a in
induced sputum in patients with stable COPD, with a
further increase during exacerbations.
• Moreover, COPD patients with pulmonary hypertension
show significantly higher TNF-α and C-reactive protein
levels than COPD patients without pulmonary
hypertension, further corroborating the role of COPD as an
inflammatory systemic disease.
• Some studies show that TNF-α blockers ameliorate
pulmonary pressure, while other studies found no

18. • Elevated serum levels of IL-2, IL-4, IL-8, IL-10, and IL-12p70 in
patients with idiopathic and familial PAH.
• IL-1, IL-6, and TNF- are elevated in PAH, confirming the results
of previous smaller studies.
• Circulating levels of IL-2, IL-6, IL-8, IL-10, and IL-12p70 had a
significant impact on survival and may prove to be important
biomarkers in risk stratifying these patients.

19. • A higher average or initial IL-2 concentration and an increase in
IL-2 concentration were associated with decrease in 30-day
mortality in patients with ARDS in ECMO.
• However additional studies are needed to evaluate the role and
therapeutic potential of IL-2 in ARDS patients on ECMO.
• No significant association was seen between serum levels of
TNF-α or IL-6 with 30-day mortality.

20. • Cytokine storm is an umbrella term encompassing several
disorders of immune dysregulation.
• No single definition of cytokine storm or the cytokine
release syndrome is widely accepted.
• It is characterized by constitutional symptoms, systemic
inflammation, and multiorgan dysfunction that can lead
to multiorgan failure if inadequately treated

21. Clinical Presentation of Cytokine Storm

23. Summary
• Distinguishing between protective inflammatory responses and
pathologic cytokine storm has important implications for
treatment and is quite challenging.
• No unifying definition of cytokine storm exists, and there is
much disagreement about what the definition should be and
whether specific conditions such as Covid-19 should be
included in the spectrum of cytokine storm disorders.
• We propose a unifying definition for cytokine storm that is
based on the following criteria: elevated circulating cytokine
levels, acute systemic inflammatory symptoms, and secondary
organ dysfunction beyond that which could be attributed to a
normal response to a pathogen, if a pathogen is present.

24. • Systematic review and meta-analysis of COVID-19 studies published or
posted as preprints between Nov 1, 2019, and April 14, 2020, in which
interleukin-6 concentrations in patients with severe or critical disease
were recorded.
• 25 COVID-19 studies (n=1245 patients) were ultimately included.

26. Key messages
• Inflammatory cytokine elevations in patients with severe and critical COVID-19,
including elevations of interleukin-6, are profoundly lower than those reported
in patients with ARDS unrelated to COVID-19, sepsis, and chimeric antigen
receptor (CAR) T cell-induced cytokine release syndrome
• In contrast, several non-cytokine biomarkers, including D-dimer, C-reactive
protein, and ferritin, are elevated to a similar or greater extent in patients with
COVID-19 than in patients with these comparison disorders
• As in other syndromes of critical illness, the role of inflammatory cytokine
elevations in the pathobiology of COVID-19 remains unclear
• The systemic inflammatory profile of COVID-19 is distinct from that of non-
COVID-19 conditions ,applying the descriptor cytokine storm to COVID-19
might be particularly problematic
• Alternative models of organ dysfunction in COVID-19, such as endovasculitis,
direct viral injury and lymphodepletion, or viral-induced immunosuppression,
might be worth considering

27. • cytokine storm is the key reason for deterioration within a short
timespan in COVID-19 patients and subsequent development into
ARDS leading to respiratory failure and eventual death from multiple
organ failure.
• Increasing evidence suggests that cytokines such as IL-6, IL-1b
receptor, IFN-g, and TNF-a play a key role in the pathogenesis of
COVID-19. Therefore, it is of great significance to accurately identify
COVID-19 inflammatory pathways and therapeutic targets.
• Although many current therapies are based on inhibiting the
occurrence and development of cytokine storms, the efficacy of the
current therapies is still unsatisfactory

28. Conclusions:
The inverse relationship between serum IL-6 and
Pao2/Fio2 and static lung compliance is specific to
SARS CoV2 infection in critically ill patients with
respiratory failure.
Similar observations were not found with IL-β or TNF-
α.

29. • PASC persists in 60% of participants up to 24
months after mild COVID-19
• PASC is associated with high IL-1b, IL-6, and TNF
levels but not autoantibodies

30. • PFCs are likely involved in pleurodesis induced by IPCs, with higher
levels of IL-8, VEGF, and bFGF in those patients who achieved auto
pleurodesis.
• Except for IL-8, the majority of PFCs demonstrated strong and
positive correlations across all measurement time points.
• This evidence is useful for further studies directed towards
developing biochemical criteria to help in the selection of suitable
candidates for pleurodesis and in developing agents that can
mediate inflammatory pathways

33. • The combination of IL-27 and ADA is more valuable in the
diagnosis of TPE compared to non-TPE than either is alone.
• The measurement of this combination of soluble mediators in
pleural fluid that provide high levels of sensitivity and specificity
for TPE
Nature research Scientific Reports | (2021) 11:660 |
https://doi.org/10.1038/s41598- 020-79685-1

34. • The Th1-dominated immune response is considered an
important factor in the containment of mycobacteria.
• This meta-analysis confirms that pleural effusions caused by
TB are predominated by Th1 cytokines.
• Slight preponderance of Th2 cytokines in MPE was not
sufficiently convincing to prove.

35. • The levels of IL-1𝛽, PAI-1 and t-PA in the pleural effusions were different
between tuberculous pleurisy and tuberculous empyema; it could be
helpful to differentiate the two diseases.
• The levels of PAI-1, IL-1𝛽 were higher and t-PA, IL-6 were lower in pleural
effusions of the patients with tuberculous empyema and who must
undergo operation than the patients who could be treated with closed
drainage and anti-TB chemotheraphy.
• These indications may be helpful to evaluate whether the patient needs
the operation.

36. Cytokines in immunology of lung transplantation
• PGD is augmented by IFN-y, IL-6, IL-8, TNF-a, and MCP-1. This
could be explained by monocyte involvement and inflammatory
changes during ischemia-reperfusion injury.
• IL-1b, IL-6, IL-10, IL-15, and IFN-γ appear to be strong indicators to
supplement the diagnosis of acute rejection in lung transplant
recipients. These cytokines are linked to a Th1 immune response
associated with acute inflammation.
• IL-1b, IL-6, IL8, IL-15, IL-17, IFN-γ, and TGF-β are significant
contributors to chronic lung allograft dysfunction.
• IL-12 has also shown to attenuate chronic lung rejection.
Cytokine Biomarkers in Lung Transplant Recipients: A
Review John Hallsten and Wickii T. Vigneswaran

37. CONCLUSION
• Cytokines and their receptors comprise a "language“
that is crucial to cellular function. Cytokines report the
presence of microbes and injured epithelia.
• More studies are needed to validate use of cytokine
assays in diagnosis of lung and pleural diseases
• Although anti-cytokine therapeutics is not yet ready
for other chronic respiratory diseases, anti-cytokine
biologics approved for severe asthma shows good
clinical outcome in appropriately selected patients

38. THANK YOU