no-see-um is a tiny fly that bites human and other warm blooded mammals. It causes a reaction that range from mild to severe and last for minutes to 2 weeks. There is no effective treatment

1. INVISIBLE BLOOD SUCKERS:
“NO-SEE-UM” (BITING MIDGE)
A NEW APPROACH TO TREATMENT
By
Kevin KF Ng, MD, PhD.
Former Associate Professor of Medicine
Division of Clinical Pharmacology
University of Miami, Miami, FL.,USA
Email: kevinng68@gmail.com
A Slide Presentation for HealthCare Providers Sept 2022

2. Presentation outline
▪ My adventures with insect stings and bites.
▪ What is “no-see-um”, the tiny blood sucking fly.?
▪ Global distribution of the “no-see-um”.
▪ Scientific classification
▪ Anatomy of no-see-um.
▪ Salivary composition of no-see-um.
▪ Reaction to no-see-um bites.
▪ Scientific clinical studies.
▪ Treatment of itch.
▪ Summary

3. My adventures with insect stings, bites and their
treatments with topical phytochemicals
https://www.slideshare.net/ssusera9ba27/presentations

4. Swarm of no-see-ums (biting midges)

5. What is “no-see-um”?
▪ “no-see-um” is abbreviated from “do not see them”
▪ No-see-um is a tiny fly (1-3 mm) that belongs to the
Ceratopogonidae (no-see-um) family of insects.
▪ Only the adult female no-see-ums bites.
▪ No-see-ums bite in swamps.
▪ Itch is the predominant symptom.
▪ There is no effective treatment.
No-see-um at dusk mosquito no-see-um

6. Common names for no-see-um in different countries
©DRKEVINNGNG

7. Differences between the bites of no-see-um and mosquito.
https://hearinghealthmatters.org/waynesworld/2011/my-battle-with-the-ear-no-see-ums-and-textbooks/

8. HABITAT OF NO-SEE-UM

9. Estimate of biting midge numbers in Scotland Highlands (2017)
▪ Biting midge is a small two-winged fly that is often seen in swarms near water or
marshy areas where it breeds.
▪ An expert on the Highland biting midge has said there could be an estimated 21 billion
female of the tiny insects in the Highlands and Islands.
https://www.bbc.com/news/uk-scotland-highlands-islands-39847894

10. Global distribution of “No See Ums”
https://a-z-animals.com/animals/no-see-ums/
The family of Diptera includes more than 5,000 species, distributed worldwide, apart from the Antarctic and the Arctic.

11. “No-see-ums” in the United States
▪ No-see-ums breed in very damp soil, mud and decaying vegetation.
▪ A single female no-see-um can breed up to 7 times per year and lay more than 400
eggs at one time.
https://bestbeebrothers.com/blogs/blog/no-see-um-season

12. • SCIENTIFIC CLASSIFICATION
• SCIENTIFIC PUBLICATIONS

13. Scientific classification of no-see-ums
▪ Ceratopogonidae is a family of flies commonly known as no-see-ums, or
biting midges, generally 1–3 mm in length.
▪ The family includes more than 5,000 species, distributed worldwide, apart
from the Antarctic and the Arctic.
▪ Size: 1-3 mm
▪ Class: Insecta
▪ Family: Ceratopogonidae; Newman, 1834
▪ Order: Diptera
▪ Kingdom: Animalia
▪ Phylum: Arthropoda

14. Number of publications “biting midge, no-see-um) in PubMed
from 1946 to 2021
https://pubmed.ncbi.nlm.nih.gov/?term=no+see+um

15. •LIFE CYCLE
•ANATOMY

16. No-see-um (biting midge) life cycle.
https://www.insectshield.com/pages/midges

17. Morphology of Culicoides midges
https://www.butox-info.com/ectoparasites/morphology-culicoides.asp
1-3 mm

18. Morphology of mouth parts of no-see-um
https://www.onlandscape.co.uk/2016/07/dreaded-scottish-midge/

19. Head and mouthparts of biting midge, Culicoides (Ceratopogonidae)
https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/mouthparts

20. How does a no-see-um bite look like?
▪ No-see-ums bite any exposed skin especially the back, neck, hands or legs.
▪ No-see-ums use the sharp, saw-like parts of their mouth to slice into the skin, causing
a mild to severe reaction.
▪ An allergic reaction to no-see-um bites can manifest as a fever, redness, swelling,
breathing problems, swollen glands, and other more severe symptoms
https://lancaster.unl.edu/pest/resources/biters.shtml https://www.ridmycritters.com/how-to-get-rid-of-no-see-ums/

21. NO-SEE-UMS: THE INVISIBLE BLOOD SUCKERS AFTER A MEAL (2017)
https://entnemdept.ufl.edu/creatures/aquatic/biting_midges.htm

22. • WHY DO FEMALE NO-SEE-UMS BITE?
• SALIVARY COMPOUNDS
• REACTIONS TO NO-SEE-UM BITES

23. Why do no-see-ums bite?
▪ No-see-ums belong to a species of tiny flies.
▪ The females need blood for reproduction.
▪ Their mouthparts include cutting teeth that break
the skin to extract blood.
▪ The bite is accompanied by the secretion of
salivary compounds which cause inflammation
https://www.insectshield.com/pages/midges

24. Components of Culicoides sonorensis salivary proteins (2014)
▪ A total of 45 proteins were identified by tandem mass spectroscopy from the seven
segments.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060021/

25. Gel separation of Culicoides sonorensis salivary proteins and
their functional classification (2014)
▪ Silver-stained gel with the most abundant proteins in each segment noted. A total of 45
proteins were identified by tandem mass spectroscopy from the seven segments.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060021/
Gel separation of salivary proteins Functional classification
Unknown

26. Cocktail of inflammatory chemicals generated by no-see-um
bites
• Amines
• Cytokines
• Chemokines
• Lipid mediators
• Peptides
• Others
©DRKEVINNGNG
Inflammatory chemicals

27. Acute inflammation caused by inflammatory mediators
Pain
Itch
Swelling
Redness
Warmth
Mediators Acute inflammation
©DRKEVINNGNG
©DRKEVINNGNG

28. Cells involved in inflammatory response
White blood cells
Platelets
Plasma
Endothelium
Nerves
Fibroblasts
©DRKEVINNGNG

29. ©DRKEVINNGNG
Mast cell structure, mediators and actions
Swelling

30. Mediators of inflammation and resolution
©DRKEVINNGNG

31. Inflammation and resolution of insect bite
http://circres.ahajournals.org/content/119/1/113.figures-only

32. • MEDICAL SIGNIFICANCE
• EXPERIMENTAL STUDY

33. Medical significance of “no-see-um” bite
Viral disease in cattle and horse
• Central and South America
• Western and central Africa,
• Some Caribbean islands
©DRKEVINNGNG
? Allergy

34. Culicoides sonorensis midge feeding on BALB/c mice (2018)
https://www.researchgate.net/figure/Granulocyte-infiltration-and-cytokine-
upregulation-in-response-to-Culicoides-sonorensis_fig4_325880281
Culicoides sonorensis midge feeding on BALB/c mice.
a 10-week-old mouse on a feeding cage containing
4-day-old female C. sonorensis midges.
b Mouse abdomen showing multiple petechial
after midge feeding.
c Subcutaneous view of skin immediately after
midge feeding (7.5×).
d Size of adult female C. sonorensis biting midge.
e Culicoides sonorensis head with splayed biting
mouthparts hypopharynx (H) and maxillary palps
(Mp) (40×)

35. Physiological and immunological responses to Culicoides sonorensis
blood-feeding: A murine model (2018)
Mast cell activation critical for innate immune response to Culicoides
sonorensis midge feeding. Ten-week-old
(a) wild type mast cell-sufficient (WBB6F1-+/+ ),
(b) mast cell-deficient (WBB6F1-W/Wv ) and
(c) mass cell-reconstituted (WBB6F1-W/Wv-R) mice 3 h post-exposure
to feeding C. sonorensis.
Midge bites (circles), areas of extensive subcutaneous hemorrhaging
(black arrowheads) and vasodilated dermal capillaries (white arrows)
are shown most prominently in both the wild type +/+ and CTMC
reconstituted W/Wv-R mice. H&E staining of micro-thin sections of
abdominal skin showing extensive erythrocytes released in the dermis
and hypodermis of wild type +/+ mice
(d) compared to deficient W/Wv (e) mice.
(f) Manual counts of fed C. sonorensis females (fully vs partially)
between wild type mast cell-sufficient (+/+), mast cell-deficient
(W/Wv), and CTMC-reconstituted (W/WV-R) mouse groups.
(Magnifications: a-c 100×, scale-bars: 100 μm; d and e 200×, scale-
bars: 50 μm). (****P < 0.0001; multiple t-tests with two-stage linear
step-up procedure [41])
https://www.researchgate.net/publication/325880281_Physiological_and_immu
nological_responses_to_Culicoides_sonorensis_blood-feeding_A_murine_model

36. Damage of abdominal dermis in BALB/c mice following
feeding by Culicoides sonorensis. (2018)
Damage of abdominal dermis in BALB/c mice following feeding by Culicoides
sonorensis. Representative images at 1–3 days post-feeding (dpf). a 1 dpf with
bite marks (circles), subcutaneous hematomas (arrowhead), and vasodilation
(arrow) 10×. b By 2 dpf, subcutaneous hematomas were clearing (arrowhead),
vasodilation was still apparent (arrow) and bite sites were diminishing except
in areas where a bite had bisected a capillary (circles) 20×. c By 3 dpf,
hematomas had largely been reabsorbed and vascular damage was restricted to
areas directly damaged during feeding (arrow) 20×. d Abdominal skin of
unexposed, naive mouse 7.5×. e H&E staining of micro-thin cross sections of
mouse skin at 1 dpf showing damage to epidermis (e) associated with
extravasated erythrocytes in the hypodermis (d) (arrow). f By 2 dpf, infiltrating
leukocytes were seen at bite sites and the majority of extravasated erythrocytes
had been cleared (arrow). g At 3 dpf, infiltrating leukocyte numbers in focal
areas decreased (arrow), but were still more prevalent than that seen in the
abdominal skin of naïve mice not exposed to feeding Culicoides midges (H).
Magnifications of e-h: 200×; scale-bars: 500 μm
https://parasitesandvectors.biomedcentral.com/article
s/10.1186/s13071-018-2935-0
days post-feeding (dpf)

37. Granulocyte infiltration and cytokine upregulation in response to
Culicoides sonorensis midge feeding is mast cell dependent (2018)
Granulocyte infiltration and cytokine upregulation in response to Culicoides
sonorensis midge feeding is mast cell dependent. Micro-thin cross abdominal
skin sections from (a) 10-week-old wild type mast cell-sufficient (WBB6F1-+/+ )
mice, (b) CTMC-reconstituted (WBB6F1-W/Wv-R) mice or (c) mast cell-deficient
(WBB6F1-W/Wv ) mice at 3 h post-feeding (hpf) by C. sonorensis stained for
chloroacetate esterase activity indicative of activated granulocytes. Insets show
degranulating mast cells. Arrows showing infiltrating granulocytes, primarily of
neutrophil lineage, were abundant in abdominal areas associated with midge
feeding in wild type and mast cell-reconstituted mice. (Magnifications: 1000×,
scale-bars: 10 μm). d Quantitative RT-PCR measuring cytokine expression in
inguinal lymph node cells of mast cell-deficient (W/Wv), mast cell-sufficient (+/+),
and CTMC-reconstituted (W/Wv-R) mouse strains at 3 hpf. Increased expression
levels (y-axis) are reported as a corrected fold difference (2-ΔΔC T ) compared to
naïve controls (basal level). Beta actin was used as an internal control.
Additionally, wild type (+/+) and reconstituted (W/Wv-R) groups were compared to
the mast cell-deficient (W/Wv) group (*P < 0.05, **P < 0.01, ***P < 0.001, ****P <
0.0001; Holm-Sidak t-test for multiple comparisons between the groups within
each cytokine)
https://www.researchgate.net/figure/Granulocyte-
infiltration-and-cytokine-upregulation-in-response-to-
Culicoides-sonorensis_fig4_325880281

38. Cytokine expression upregulation in inguinal lymph nodes in
response to Culicoides sonorensis midge feeding (2018)
Cytokine expression upregulation in inguinal lymph
nodes in response to Culicoides sonorensis midge
feeding. Quantitative RT-PCR was used to measure
cytokine expression in inguinal lymph node cells at 1, 2
and 3 days post-feeding (dpf) by C. sonorensis.
Increased expression levels (y-axis) are reported as a
corrected fold difference (2-ΔΔC
T) compared to naïve
controls (basal level). Beta actin was used as an internal
control
https://parasitesandvectors.biomedcentral.com/article
s/10.1186/s13071-018-2935-0

39. CLINICAL STUDY

40. What Do no-see-um (biting midge) bites look like?
Like mosquito bites, midge bites often cause irritation
and leave tell-tale signs:
1. Clusters of red dots
2. A small hole in the middle of the bite where skin
was punctured
3. Some reactions to midge bites can be severe:
People who are sensitive to insect bites may feel a
burning sensation followed by red welts on their
skin.
4. People who are extremely sensitive to bites may
develop painful, itchy blisters filled with fluid
5. Itch is the predominant symptom
https://www.insectshield.com/pages/midges

41. Reactions to no-see-um bites
Common reaction Allergic reaction Infected bites

42. Reaction of women and men to midge bites (2010)
Adapted from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893461/

43. Severity and duration of no-see-um bites in human
Adapted from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2893461/

44. HOW TO TREAT NO-SEE-UM BITES ?

45. Insect
saliva Skin
Inflamation
Pain
Warmth
Redness
Swelling
Itch
Interaction of no-see-um saliva and skin
©DRKEVINNG

46. Source of chemical mediators in Inflammation
Result
Source
 Cellular injury
 Nerves
 Blood vessels
 White blood cells
 Platelets
 Plasma
Mediators ( > 20 )
Amines
Cytokines
Chemokines
Lipid mediators
Free radicles
Peptides
INFLAMMATION
Pain
Swelling
Redness
Warmth
Itch
©DRKEVINNG

47. Mediators blocked (X) by synthetic antihistamine,
hydrocortisone and NSAIDS
Result
Source
 Cellular injury
 Nerves
 Blood vessels
 White blood cells
 Platelets
 Plasma
Mediators ( > 20 )
Amines
Cytokines
Chemokines
Lipid mediators
Free radicles
Peptides
INFLAMMATION
Pain
Swelling
Redness
Warmth
Itch
X
X
Many chemical mediators are not targeted
©DRKEVINNG

48. Phytochemicals that block the inflammatory process
caused by no-see-um bites
▪ Flavonoids Berries
▪ Curcumin Turmeric
▪ Piperine Black pepper
▪ Gingerol Ginger
▪ Capsaicin Chili pepper
▪ Boswellic acid Frankincense
Phytochemicals Source

49. Scientific approach to treatment of no-see-um bites.
▪ A variety of home remedies and over-the-counter medicinal products are available
for the topical treatment of no-see-um bites.
▪ However, no controlled clinical trials have been reported.
▪ The current knowledge of anti-inflammation by phytochemicals has outpaced the
use of conventional topical products.
▪ I have developed a topical remedy from herbs and spices to target the chemical
mediators of no-see-um bites.
▪ Results showed that the phytochemical extracts relieved the itch faster and more
effectively than conventional antihistamine and hydrocortisone preparations.
▪ If you are interested in this invention, please contact me for further information.

50. Summary
▪ No-see-um is a tiny fly know as biting midge.
▪ It is 1-3 mm in length and is found in all continents except the artic and antarctica
▪ Only the adult female no-see-um bite and suck blood from human being and other
warm- blooded animals.
▪ The reaction to the no-see-um bites leads to the release of multiple chemical
mediators which cause pain, itch, swelling and warmth.
▪ Current anti-itch topical and oral remedies are ineffective for symptom relief.
▪ Natural phytochemicals extracted from herbs and spices have been shown to
provide faster and more effective relief from itch than conventional products.
▪ If you are interested in this invention, please contact me for further information.

51. ANY QUESTIONS?
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