Pelargonium sidoides

Pelargonium sidoides (of the family Geraniaceae) is a plant initially from the Eastern Cape Province of South Africa and dubbed South African Geranium which has popular usage for the treatment of respiratory related ailments, such as bronchitis and asthma.^[1][2] It comes from a relatively large genera (270 species under the name of pelargonium) but can readily be distinguished by the cordate shape of the leaves and the dark red, but commonly almost black flowers borne on long, slender stalks;^[3] its roots are dark externally and red internally.^[4] It's usage as a traditional medicine is for respiratory ailments, general sickness, fatigue, menstrual complaints, and it bears the names of rabas or 'Umckaloabo' traditionally^[5][6][4] while its modern day usage as a phytopharmaceutical (mostly in Germany) is under the brand name Umckaloabo® (ISO Arzneimittel, Ettlingen, Germany) which is physician prescribed for acute bronchitis^[7] and is known in France under the brand name of Kaloban.^[8]

This plant appears to be classified as 'declining' on the Red List of South Africa plants (2009), suggesting that while it is currently not endangered it is at risk of it.^[1][9]

This medicinal plant does not appear to be sustainable at this moment in time assuming standard growing, harvesting, and preservation techniques due to its high demand

The roots of this plant contain:

• Coumarins (synonymous with benzopyranones) including 5,6,7-trimethoxycoumarin, 6,8-dihydroxy-5,7-dimethoxycoumarin, scopoletin (7-Hydroxy-6-methoxycoumarin), umckalin (7-Hydroxy-5,6-dimethoxycoumarin at 0.041% dry weight^[10]),^[11][3] 7-Acetoxy-5,6-dimethoxycoumarin, 7,8-Dihydroxy-6-methoxycoumarin (Fraxetin), and 5,6,7,8-Tetramethoxycoumarin (Artelin)^[3][12]

• Coumarin glycosides Magnolioside, Isofraxoside, and Umckalin-7-β-d-glucoside^[3]

• Coumarin sulfates 5,6-Dimethoxycoumarin-7-sulfate, 6,7-Dimethoxycoumarin-8-sulfate, 8-Hydroxy-5,7-dimethoxycoumarin-6-sulfate, and 6-Hydroxy-5,7-dimethoxycoumarin-8-sulfate;^[3][6] these sulfated coumarins (collectively with the glycosides and aglycones of coumarins) consist of up to 0.2% of the root by dry weight^[13] gallocatechin, and epigallocatechin^[14]

• Catechin dimers (Prodelphinidin B2 isomers) including epigallocatechin-(4β→8)−gallocatechin, epigallocatechin-(4α→8)−epigallocatechin, gallocatechin-(4β→8)−gallocatechin, and gallocatechin-(4α→8)−epigallocatechin;^[14] alongside some A-type prodelphinidins and the relatively unique gallocatechin-(4α,8)-epigallocatechin^[15] (also found in Trifolium repens^[16] and the ribes species^[17])

• Catechin trimers up to hexamers have been reported^[18]

• Gallic acid and gallic acid methyl ester^[11]

• Shikimic acid 3-O-gallate^[3]

• β-Sitosterol^[3]

There is a collection of molecules known as Prodelphinidins in pelargonium sidoides which refers to any oligomer (dimer or larger) containing gallocatechin, and as such the catechin dimers such as epigallocatechin-(4β→8)−gallocatechin or gallocatechin-(4β→8)−gallocatechin are considered Prodelphinidins; this is because under oxidative conditions, these molecules depolymerize to give of the anthocyanin known as delphinidin. This concept is similar to the catechin oligmers called procyanidins (found in pycnogenol or grape seed extract) depolymerizing to form cyanidin.

Unlike other plants in the pelargonium genera, sidoides does not appear to have a detectable content of small phenolic acids (caffeic, ferulic, protocatechuic, coumaric) and its shikamic acid is fully gallated;^[3] it also appears to be somewhat devoid of the typical flavonoids kaempferol, quercetin, and myricetin.^[3] Pelargonium sidoides is sometimes adultered with the related plant pelargonium reniforme which has widely different bioactives^[3] but can be distinguished easily by its lack of umckalin.^[19]

The roots appear to contain a variety of gallated catechins (gatechin structures with a gallic acid group attached to them, sort of like the green tea catechins) in such a structure that they are called Prodelphinidins. There is also a coumarin and tannin content which are seen as benficial but secondary to the prodelphinidins

The aerial parts of this plant (leaf and stem) include:

• Gallic acid and both its methyl and ethyl esters^[3] and its β-D-glucoside (Glucogallin)^[3]

• Shikimic acid 3-O-gallate^[3]

• Coumarins Scopoletin, Umckalin, Fraxetin and its Fraxetin-7-β-d-glucoside, Magnolioside^[3]

• Quercetin^[3]

• Dihydrokaempferol 3-O-β-d-glucoside^[3]

• Taxifolin-3-O-β-d-glucoside^[3]

• Luteolin 7-O-β-d-glucoside^[3]

• Vitexin and its 2″-O-gallate and Isovitexin with its 2″-O-gallate^[3]

• Orientin and Isoorientin with their 2″-O-gallates^[3]

• Epigallocatechin-3-O-gallate^[3]

• (+)-Cyclolariciresinol-2a-β-d-glucoside^[3]

• 4,6-Dihydroxyacetophenone 2-O-β-d-glucoside^[3]

• 4-Allyl-2,5-dimethoxyphenol-1-β-d-glucoside^[3]

The aerial parts of the plant seem to not possess the delphinidin structures but retain the coumarin structures; the flavonoids that are absent in the root are present in the aerial parts in various gallated forms

There is a patented production known as Umckaloabo® (ISO Arzneimittel, Ettlingen, Germany) of which contains a standardized pelargonium sidoides extract known as EPs7630® and appears to be popular for the treatment of respiratory tract infections.^[20][21]

The liquid version of EPs7630 is an 11% ethanolic extract of the roots of pelargonium sidoides, and is concentrated 8-10 times (1:8-10 extract) when put into liquid solution; a 50mL bottle is equivalent to 8g of pelargonium sidoides roots by weight, and the recommended dose to be taken thrice daily (4.5mL) is equivalent to 720mg of the root.^[20] There is also an encapsulated extract of the same concentration (1:8–10 extract of 11% ethanol) where 20-30mg taken thrice daily (equivalent to around 160-300mg of the root per capsule) appears to be effective.^[22]

EPs7630 contains all the coumarins and catechin structures that the root extract does except for isolated catechin and gallocatechin (prodelphinidins are still included) and the sulfated coumarins are absent;^[3] the coumarins and prodelphinidins, alongside the benzopyranones, make up 70-80% of the weight of EPs7630.^[23]

In studies that quantify components of EPs7630 or similarly extracted tinctures, it is noted that there is a umckalin 21.04-21.58μg/mL.^[24]

The patented formulation known as EPs7630 is an 11% ethanolic extraction where 10 drops (or 10mg of a capsule) are equivalent to around 300mg of the root of the plany; it is by far the most frequently used product in the human studies on pelargonium sidoides

One study administrating an 11% root ethanolic extract has detected a coumarin structure (one hydroxyl and two methoxyl groups; thought to be umckalin) in serum within an hour; it was not quantified.^[25]

Supplementation of EPs7630 to rats (10-500mg/kg) over the course of two weeks or acutely alongside warfarin does not influence serum pharmacokinetics of warfarin nor does it influence the blood clotting potential of it.^[26]

Does not appear to interact with warfarin pharmacokinetics or blood clotting, which usually occurs with coumarin based compounds

Adaptogenic compounds are those that regulators that increase the ability of an organism to adapt to environmental stressors and avoid damage to the organism from said stressors; more scientifically, they increase nonspecific resistance to stress,^[27][28] regulate bodily function with a focus on corticosteroid hormones and the hypothamalic/pituitary axis,^[29] and seem to pharmacologically target neuropeptide Y (NPY) and heat shock protein 72 (Hsp72).^[30] 

While not traditionaly used as an adaptogen, pelargonium sidoides appears to have traditional usage as a tonic and a 40% ethanolic extract (41.2% polyphenols) failed to have an influence on NPY while it reduced Hsp72 in human neuroglial cells (62.1+/-0.5%) and in primary neurons (34.3+/-12.2%).^[30]

No detectable antistress or adaptogenic potential of this plant, although it is not particularly well studied in this regard either

Preliminary CNS screening of the catechin and prodelphinidin oligomers in pelargonium sidoides has failed to find any analgesic effect on a hot plate test.^[18]

No notable analgesic properties of this plant in the preliminary animal evidence

In a study on upper respiratory tract infections in children, EPs7630 at the standard child dose (10 drops thrice daily) was unable to significantly reduce the fever over the course of one week despite improvements in appetite and nasal congestion^[31] and this lack of fever reduction has been noted elsewhere with viral upper respiratory tract infections.^[32]

In studies on acute bronchitis, however, fever tends to be improved relative to placebo with around 80-90% of persons reporting a lack of fever after a week of supplementation whereas placebo tends to report full resolution of fever in 50-70% of persons;^{[33][34][35][36][20][37]} the lone study on the common cold that had fever associated with it noted that, alongside improvements in the symptoms of the common cold, were improvements in fever with supplementation relative to placebo.^[38]

Fever as a side-effect of acute bronchitis appears to be reduced

In both acute bronchitis^[39][40] and upper respiratory tract infections,^[31] the reduced appetite seen with both disorders appears to be significantly improved.

When appetite is reduced as a side-effect of sickness, it appears that supplementation can increase appetite; this has been noted in instances of upper respiratory tract infections as well, suggesting it may not be exclusive to acute bronchitis

The nausea associated with acute bronchitis was found to not be significantly improved after a week in youth, although this study also failed to note a benefit to headaches which tend to be positively affected;^[40] studies in youth that do report benefits to headache symptoms (alongside overall improved symptoms) have noted improvements in nausea.^[39]

When fever and headaches are helped secondary to treating the sickness, nausea tends to follow suit; if there are no improvements in headache symptoms then the nausea is not significantly improved

One study in acute bronchitis has failed to find a significant reduction in headache as a symptom of sickness with the standard dose of EPs7630 relative to placebo in youth^[40] although this is not always the case, as benefit has been reported in youth being treated for acute bronchitis.^[39]

There may be a reduction in headaches associated with the treatment of acute bronchitis

Preliminary pharmacological screening of pelargonium sidoides prodelphinidin molecules in mice has failed to demonstrate an anti-depressive effect (as assessed by the forced swim test).^[18]

A preliminary study in mice assessing the neurological effects of this plant failed to find antidepressive effects of the main bioactives

Prolonged endurance exercise is known to reduce salivary levels of Immunoglobulin A which are correlated with overtraining (causation not proved and currently thought to just be a biomarker),^[41][42] and supplementation of 30 drops thrice daily of an 11% ethanolic extract similar to EPs7630 for 28 days in marathon runners is able to reverse a 60% decline seen in placebo to a 194% increase.^[25]

The exercise induced increases in IL-6 and IL-15 have been noted to be prevented with supplementation as well, resulting in similar concentrations before and after exercise.^[25]

The alterations in cytokine and Immunoglobulin profiles seen indicate that this herb may be useful in preventing exercise-induced immunosuppression, but more studies are required on this (particularly one measuring actual sick days)

In osteosarcoma cells (MG 63), EPs7630 appears to augment the IFN-β production from other agents (such as the viral double-stranded RNA analogue polyinosinic acid:polycytidylic acid used) without inherently stimulating IFN-β production; maximal activity reaced 200% of control 3μg/mL.^[10]

In male marathon runners given the standard supplemental dose, the salivary Imunoglobulin A (IgA) concentrations that normal decline (placebo group experiencing a reduction from 241.1μg/mL to 96.55μg/mL; 60%) appeared to increase from 132.3μg/mL before the run to 389.9μg/mL (194% increase).^[25]

There appear to be positive influenced on immunoglobulin levels (increases IgA by currently unknown mechanisms) and interferon beta production (augments the increase in IFN-β production that occurs as a natural response to viral infection)

One study used an extract similar to EPs7630 (11% ethanolic root extract of 1:9-11 concentration, equivalent to 825mg of the root extract and standardized to 0.08–0.32% phenolics) at 30 drops thrice daily for a month to male marathon runners without allergic conditions and maintaining their normal routines; it was found that that the exercise-induced increases in IL-6 (39%) and IL-15 (115%) seen in placebo were prevented.^[25]

The exercise induced increases in IL-6 and IL-15 appear to be prevented with daily supplementation of this herb; this is thought to underlie a possible reduction in excessive inflammation or overreaching seen with exercise

In cells sensitive to cytotoxicity from viruses (EMCV-sensitive L929 cells) treated with pelargonium sidoides root extract, there appears to be full protection at concentrations as low as 1.6μg/mL with increased viability up to 200% of control with concentrations of 3.12-6.25μg/mL (plateauing up until 100μg/mL) which is not due to the tested coumarins or gallic acid;^[10] this has been replicated elsewhere.^[43]

Cells that are sensitive to viruses appear to have enhanced viability in the presence of EPs7630. This may be related to the antiviral properties of the herb (reducing adsorption of the virus into said sensitive cells)

The survivial of Leishmania donovani in macrophages is reduced by pelargonium sidoides extracts despite no direct activity on the protozoan with an EC₅₀ value in the range of 2.7–3.3μg/mL (n-butanolic and methanolic) or less than 0.1μg/mL (petrol ether and ethyl acetate), with isolated gallic acid having an EC₅₀ of 4.4μg/mL and all tested coumarins ineffective.^[44] In these macrophages, EPs7630 at 50μg/mL is able to increase iNOS expression in response to leishmania donovani and subsequently increase the mRNA of TNF-α, various cytokines (IL-1, IL-2, IL-18) and interferons (IFN-α and IFN-γ); this was also seen with 250μM gallic acid and the components of a methanol insoluble fraction (but not umckalin nor molecules soluble in methanol);^[45] this increase in the immunological response to bacterial infection has been replicated against leishmania donovani at a lower concentration (3-10µg/mL).^[43]

In bone derived macrophages infected with another bacteria (Listeria monocytogenes) this augmentation of nitric oxide production (from the iNOS increase) and subsequent secretion of IL-1, IL-12, and TNF-α still applies in a concentration dependent manner in the 1-30μg/mL range.^[46] Mycobacterium such as mycobacterium tuberculosis and fortuitum have also been noted to have their macrophage-mediated destruction increased in the presence of this root extract, and it appeared that gallic acid itself was effective at the concentration of 2.5μg/mL.^[47]

Macrophages infected with bacteria appear to have significantly enhanced phagocytosis (consumption of bacteria) and killing potential (destroying the bacteria) when they are incubated with low concentrations of EPs7630. This is inherently an immunostimulatory effect that is not necessarily inflammatory, and is similar to what is seen with Tinospora cordifolia supplementation

Neutrophils are another type of immune cell able to hunt pathogens and destory them (via a process known as oxidative burst),^[48] and their activity (both phagocytosis and oxidative burst) is increased in a concentration dependent manner in the range of 3-30μg/mL when incubated alongside candida albicans;^[49] intracellular killing capacity of these cells also increased at the highest tested concentration (30μg/mL).^[49]

Similar to macrophages, neutrophils also appear to have their cytotoxicity towards bacteria enhanced in the presence of EPs7630

In children who already had viral upper respiratory tract infections who were then given the standard dosage of EPs-7630, there was no significant reductions in fever but there were some improvements in cough and nasal congestion and mostly notably a significant reduction in asthmatic attacks.^[32]

While no inherent anti-asthmatic properties have been confirmed, the increase in asthmatic attacks seen in sick persons (who have asthma in general) may be attenuated

Pelargonium sidoides appears to be commonly used not so much for the prevention of colds but rather to reduce symptoms of the cold or flu, namely respiratory symptoms.^[50]

In persons who have reported symptoms of the cold for 24-48 hours and were then given the standard dose of EPs7630 (30 drops thrice daily) for up to 10 days, it was noted that the rate of subjects who were clinically cured after ten days was more than twofold higher in the treatment group (78.8%) than it was in the placebo group (31.4%);^[38] when symptoms were measured after five days, the treatment reported 82% reductions in overall symptoms whereas placebo reached 45% symptom reduction.^[38]

The lone study assessing the common cold has found significant reductions in symptoms, where the rate of symptom reduction and the rate of being clinically cured were more than two-fold higher after a week with supplementation relative to placebo

Methanolic and acetone extracts of the roots and leaves of the plant have been noted to have minimum inhibitory concentrations (MIC values) against a variety of bacteria in vitro in the range of 2.5-7.5mg/mL such as the gram negative Salmonella pooni and the gram positive Streptococcus pyogenes, Micrococcus kristinae, Staphylococcus aureus, and Bacillus cereus while Staphylococcus epidermidis appeared a bit more resistant; the gram negative bacterium escherichia coli, Serratia marcescens, Pseudomonas aeruginosa, and Klebsiella pneumonae were unaffected.^[9] This potency has been noted with aqueous acetone extracts elsewhere (EPs7630) with particular efficacy (3.3mg/mL) against Proteus mirabilis and all tested Staphylococcus strains.^[10]

100% aqueous extracts of the plant (both roots and leaves) have failed to possess antimicrobial activities up to 10mg/mL in vitro in some studies^[9] although elsewhere they have been noted to be effective (0.6mg/mL).^[11] The hydroalcoholic extract has weak inhibitory properties on mycobacterium tuberculosis (MIC 5,000μg/mL)^[51] and EPs7630 at 12.5mg/mL has been noted ex vivo to inhibit 96% of m. tuberculosis growth.^[10]

The coumarins and tannins (but not catechins) appear to have MIC values in isolation in the range of 200-1,000µg/mL^[11] with a slightly larger range (200-2,200µg/mL) reported elsewhere.^[10]

When looking at direct antibacterial effects, while the extracts of pelargonium sidoides seem to be effective they are not overly potent and seem to work better against gram positive bacteria. The antibacterial properties of this root appear to be indirect (working via other means) rather than directly cytotoxic to bacteria

In a group A-streptococci (GAS) model of bacterial adhesion, it was noted that EPs7630 (3-30μg/mL but not 300ng/mL) was able to concentration dependently reduce bacterial adhesion to human laryngeal (HEp-2) cells up to 46% (despite the MIC being 64μg/mL) which seemed to be due to influencing the bacteria rather than the cell^[52] and a specific rather than nonspecific inhibition.^[53] When testing catechins and prodelphinidins in isolation this interaction with the bacterial outer membrane was again noted with isolated epicatechin, epigallocatechin, and epigallocatechin gallate (EGCG) at 30μg/mL;^[15] procyanidins appeared ineffective while prodelphinidins were significantly more effective,^[15] and altering the EPs7630 extract for a higher prodelphinidin content increases the inhibitory potential of this extract on bacterial adhesion.^[53] It also appears that this anti-infective property differs from that of cranberry proanthocyanidins (A-type oligomers) as they were ineffective in this assay while prodelphinidins from ginkgo biloba or procyanidins from the salix^[54] and betula^[55] species as well as Nelia meyeri^[56] were effective in a manner similar to pelargonium sidoides.^[53]

Invasion into HEp-2 cells with 30μg/mL of EPs7630 is also reduced in a time dependent manner.^[52]

When using buccal epithelial cells (BEC) instead of HEp-2, adhesion appears to be enhanced significantly;^[52] this phenomena is noted elsewhere^[57] and is thought to be due to specific binding (HEp-2) versus nonspecific binding (BEC).

EPs7630 appears to interact with the invading bacteria (rather than the endogenous cells) and reduces specific binding of bacteria to the cell. This interference with bacterial adhesion to the cell is thought to underlie the antibacterial properties of this herb, since it is quite weak in destroying the bacteria

In transient hypogammaglobulinemia of infancy (a prolongation of the normal period where material immunoglobulin production declines for the infant's to increase and sustain itself but infants tend to get more upper respiratory tract infections during this period^[58]) children between 1-5 years with upper respiratory tract infections given 10 drops of EPs7630 thrice daily for a week was able to improve nasal symptoms and improve appetite but was unable to benefit cough or fever.^[31]

In persons with acute rhinosinusitis (of probable bacterial origin) given a double dose of the standard EPs7630 tinctures (60 drops or 3.0mL thrice daily) over the course of a week was associated with significantly less symptoms of rhinosinusitis than was placebo.^[59]

In situations (not acute bronchitis) which are associated with likely bacterial infections causing issues, supplementation of the standard doses of pelargonium sidoides appears to be more effective than placebo at reducing symptoms of sickness associated with said infection

In MDCK and A549, EPs7630 appears to have an EC₅₀ value of 6.6μg/mL for inhibiting H1N1 proliferation (full inhibition at 50μg/mL) with a selective cytotoxicity index of 84.4;^[14] it failed to inhibit unenveloped adenovirus type 5 (ATCC) or enveloped measles, and appeared to work via inhibiting hemagglutination and neurneuraminidase induction by the virus associated with the polyphenolic content (since EC₅₀ values were reported to be quite low for Gallocatechin-(4β→8)−gallocatechin and Epigallocatechin-(4β→8)−gallocatechin at 11.9μM and 10.3μM, respectively)^[14]

When tested in vitro at concentrations up to 100μg/mL, EPs7630 is able to inhibit viral replication and reduce viral titres of seasonal influenze strain H1N1 (IC₅₀ of 9.45+/-2.94μg/mL and therapeutic index (TI) of 10.6; complete suppression) and H3N2 (8.66+/-1.06μg/mL and TI of 11.5; complete suppression), respiratory syncytial virus (19.65+/-1.77μg/mL and TI of 5.1; complete suppression), human coronavirus (44.50+/-15.84μg/mL and TI of 2.3; 10-fold suppression), parainfluenza virus (74.35+/-17.89μg/mL and TI of 1.3; 150-fold suppression), and coxsackie virus (14.80±3.39μg/mL and TI of 6.8; 10,000-fold suppression).^[60] Pelargonium sidoides has failed to influence the replication of highly pathogenic avian influenza A virus (H5N1), adenovirus, or rhinovirus up to 100μg/mL.^[60]

This is thought to underlie the potent effects on acute bronchitis, since up to 90% of cases of acute bronchitis are thought to have a viral origin.^[61]

Pelargonium sidoides appears to have direct inhibitory properties on viral replications, with more promise on some strains of seasonal influenza (H1N1 and H3N2) but not avian influenza (H5N1) and good promise on respiratory syncytial virus (RSV)

Pelargonium sidoides (80% methanolic extract) appears to inhibit viral replication of herpes simplex viruses (HSV1 and HSV2) as assessed by plaque formation, with the IC₅₀ values being 0.00006% and 0.000005% of the medium;^[62] this was noted to only occur when preincubated (prior to adsorption) as both HSV-1 (0.0003%) and HSV-2 (0.00003%) had 99% of their titres inhibited with the aforementioned concentrations of pelargonium sidoides.^[62]

Appears to be quite potent at inhibiting viral replication or herpes simplex associated with preventing adsorption of the virus (more of a preventative than a therapeutic role)

In mice infected with an H1N1 strain (A/Puerto Rico/8/34) given 5mg/kg EPs7630 orally thrice daily for 10 days or the same dose via inhalation, there appears to be significantly increased survival relative to control.^[14]

The antiviral effects appear to persist in mice when given the herb orally (and it is thought to be highly active in humans due to acute bronchitis mostly being a viral infection)

Pelargonium sidoides roots possess anti-adhesive properties against helicobacter pylori when EPs7630 is tested in vitro which appears to be more effective than bladderwrack and polysaccharides from licorice^[63] and prevents adhesion to stomach epithelial cells in the concentration range of 1-10,000µg/mL in a concentration-dependent manner^[64] although lower concentrations seem to be sufficient since, in isolated gastric epithelial AGC cells treated with 50-100µg/mL EPs7630, there is 77-91% inhibition of helicobacter pylori adhesion.^[65]

Similar to other bacterial strains, pelargonium sidoides has little to no direct cytotoxicity on the helicobacter pylori bacteria.^[64]

There may be a role for pelargonium sidoides in the prevention of ulcers induced by the bacteria helicobacter pylori which is different from the standard anti-ulcer approach from nutritional supplementation (ie. a hefty dose of antioxidants to reduce the damage to the stomach wall). Both human and animal studies are lacking at this moment in time

Acute bronchitis is a common lower respiratory tract infection that, for about 90% of cases, is thought to have viral origins^[66][67] and is characterized by excessive coughing and sputum in the lungs which causes a coarse snoring-like sound (sometimes called rales or rhonchi).^[68] It is one of the top ten reasons patients seek medication from a doctor^[69][66] and despite being thought to usually not be bacterial in nature, it is usually treated with antibiotics (65-80% of cases^[70][66]); pelargonium sidoides is thought to be beneficial due to it traditionally being used for this condition, and having both potent anti-viral properties against most lung viral infections ex vivo^[60] and antibacterial properties that reduce adhesion^[53][52] and are thought to be less likely to cause bacterial resistance problems since they are not necessarily cytotoxic to the bacteria.

Diagnosis of acute bronchitis tends to focus around hoarse coughing (85% of patients reporting a cough within two days, and mostly gone by two weeks but has been noted to persist for 8 weeks in a few patients); usually alongside the cough there exists hoarseness, rhonchi (a hoarse snore-like sound from the lungs caused by sputum buildup), and vitality symptoms like fatigue, fever, and general malaise.^[66]

Acute bronchitis is a conditions characterized by hoarse coughing, wheezing, and sputum buildup in the lungs that can cause something like a snoring sound in the lower lungs (rhonchi) that usually lasts just over two weeks but may persist for a month of longer in a select few patients

In adults with acute bronchitis given supplemental pelargonium sidoides (EPs7630) at thirty drops thrice daily for one week and assessed by the Bronchitis Severity Score (BSS) (validated subjective measure for acute bronchitis^[71]) noted that the improvement in symptoms over one week seen with the supplement (8.4 on the rating scale to 2.5 on average; 70% reduction) exceeded that of placebo (8 down to 4.8; 40% reduction) with improved symptoms occurring at the first followup of 3-5 days.^[20] EPs7630 was also more effective at lowering the rating below 3 (64.4% of EPs7630 and 37.9% of placebo) and in inducing a 7 point reduction on the scale (43.3% of EPs7630 and 23.0% of placebo), and in 77.1% of treatment group rhonchi (coarse rattling in airways from secretion) was abolished alongside cough (83.7% of treatment) and fever (96.9%).^[20] Elsewhere, adults with acute bronchitis given a similar protocol (4.5mL thrice daily for a week and assessed by the BSS in a double blind manner) replicated such a reduction in overall symptoms of bronchitis and improved self-reported quality of life relative to placebo.^[36]

Once study that encompasses both adults (30 drops thrice daily) and children (20 drops thrice daily if between 6-12yrs, 10 drops thrice daily for those under six) over two weeks was able to significantly reduce overall scores on the BSS in all age groups, with a 86% reduction in the entire sample with a similar magnitude in children (86%) and those under three years of age (77%).^[35] In both adults and children, this study also confirmed large reductions in the comorbidities of acute bronchitis including reductions in fever (94.6%), chest pain when coughing (94.1%) and the cough itself (59.7%), fatigue (80.2%), rhonchi (93.1%) and sputum (80.7%), headache (90.7%), and shortness of breath (93.2%) after two weeks.^[35] Efficacy in children of all age groups (0-18) is similar to the efficacy seen in adults.

When looking the course of treatment, it appears that benefits may come within two^[37] or three^[20] days of supplementation but are greater at day seven (relative to day three)^[20] and are greater after two weeks relative to one;^[35] this suggests time-dependent benefits up until two weeks where symptoms are mostly abolished. Dosage wise, in adults given supplements of either 10mg thrice daily, 20mg thrice daily, or 30mg thrice daily it seems that while 20-30mg thrice daily (60-90mg each day) is slightly better than 10mg that there is no difference between the two higher doses and that all are better than placebo.^[22] When comparing the efficacy of EPs7630 against other conventional therapies, a meta-analysis^[72] (referencing a one study behind a language barrier) found that 30 drops of EPs7630 thrice daily is nonsignificantly better than 200mg of N-acetylcysteine twice daily in children for treating symptoms of acute bronchitis after seven days (although symptoms were cleared up faster with EPs7630).

In both children and adults specifically with acute bronchitis, supplementation of the standardized extract of pelargnoium sidoides appears to be highly effective in reducing respiratory side-effects

One study has been conducted in bronchitis in general (acute bronchitis, but also persons with chronic bronchitis experiencing an acute increase in symptoms) with the standard 30 drop thrice daily dosing schedule of EPs7630 noted whole-group improvement; while there wasn't a large sample of persons with acute bronchitis given supplementation (n=19) there did not appear to be any difference in the benefits achieved.^[37]

Appears to also be beneficial for those with chronic bronchitis experiencing a short term increase in symptoms, but the body of evidence is less robust for this specifically

In adults with chronic obstructive pulmonary disease (COPD; characterized by limited airflow associated with inflammation^[73]) given 30 drops of EPs7630 daily over the course of 24 weeks noted that there was a significantly reduced need for antibiotic treatment (73.3% in placebo and 37.8% in EPs7630) and improved breathing as assessed by the SGRQ (St. George's Respiratory Questionnaire^[74]) and the reduced exacerbations of symptoms.^[21]

There appears to be benefit to adults with COPD (impairment of lung function not associated with viral infections, but with inflammation) by reducing the need for subsequent antibiotic treatment and reduced exacerbations of symptoms

30 drops of EPs7630 (4.5mL) thrice daily for a week alongside meals is not associated with any more side-effects than placebo^[20] and this same dose extended to 24 weeks in persons with COPD is similarly free of side-effects relative to placebo overall, although the authors noted a causal relationship in a few persons could not be ruled out.^[21] One of the larger studies on the subject matter (those with acute bronchitis; sample size of 2099) found adverse effects reported in 1.2% of persons on supplementation but this was not significantly different than placebo.^[35]

When prescribed by physicians, pelargonium sidoides appears to be the alternative medication most commonly associated with adverse effects at 0.21% of prescriptions (4 of 1,940) of which all were deemed to be nonserious and treated with cessation of the medication;^[7] the side effect frequently was still lower than some standard medications such as N-acetylcysteine (0.5%) and antibiotics yet less than paracetamol (0.04%).^[7]

Studies in children specifically (ages between 0 and 18) have failed to note any unique toxicological effects for their age group, and it appears to be equally well tolerated.^[40][35][39] It is similarly well tolerated if the dosage is extended to two weeks^[35] or even a month,^[25] and a week of supplementation at double the dose in adults (60 drops thrice daily) has been well tolerated.^[59] 

Supplementation of the standardized extract of EPs7630 appears to be very well tolerated for periods of up to a month, and supplementation of double the standard dose for a single week has also been very well tolerated. Higher doses and longer supplementation times are thought to be equally well tolerated but have not been sufficiently studied

There have been sporadic reports of hepatotoxicity associated with supplementation of pelargonium sidoides in Germany where it is prescribed as a medication, although it appears that causality is lacking in the majority of cases.^[75][76]

Similar to most popular supplements (such as black cohosh or kava) pelargonium sidoides appears to be associated with isolated cases of liver toxicity which, at this moment in time, have not established a causative relationship between the herb itself and the toxicity to the liver

There have been reports that usage of pelargonium sidoides (as a phytopharmaceutical) have induced allergic reactions of which there have been 34 reports over the course of four years (2002-2006) in Germany.^[77] Most common reported reactions were a rash and urticaria as well as respiratory reactions; usually the reactions occur on the first day of supplementation, and most were confirmed by pharmacists.^[77]

It appears possible to be allergic to this herb, and the frequency of allergies is not known nor is the particular antigen in the herb that is causing said reactions