Allergic Rhinitis and Asthma - Royal Children's Hospital

Department of Allergy and Immunology

Allergic Rhinitis and

Asthma

Dean Tey

Paediatric Allergist & Immunologist

Royal Children’s Hospital

FRACP LECTURE 2014


Allergic rhinitis

1. Background

2. Types of rhinitis

3. Pathophysiology

4. Classification

5. Clinical assessment

6. Investigations

7. Management


Beasley et al. Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of

Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 351 (9111):1225-32, 1998.


1. Beasley et al. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet 351 (9111):1225-32, 1998.

2. The economic impact of allergic disease in Australia: not to be sneezed at. Access Economics for ASCIA, 2007.

http://www.allergy.org.au/images/stories/pospapers/2007_economic_impact_allergies_report_13nov.pdf . Accessed 6 November 2010.

AR1,2

● Rank #7

● M 15.6%

● F 16.6%

● Dominant

allergy in

25-34yo

Asthma1,2

● Rank #3

● M 7.8%

● F 9.6%

● Dominant

allergy in

<14yo

http://www.allergy.org.au/images/stories/pospapers/2007_economic_impact_allergies_report_13nov.pdf


Gupta, R., A. Sheikh, et al. (2007). "Time trends in allergic disorders in the UK." Thorax

62(1): 91-6.

UK Serial health surveys●Lifetime prevalence of AR and eczema trebled over

last 3 decades

●Rate of increase declined since the latter part of

1990’s


Allergic rhinitis

1. Background


3. Pathophysiology

4. Classification


6. Investigations

7. Management


A. Allergic rhinitis (50-70%)

B. Occupational

C. Non-allergic rhinitis

1. Infectious – viral, bacterial, other

2. Drug-induced

Aspirin-exacerbated respiratory disease

Rhinitis medicamentosa

4. Non-allergic rhinitis with eosinophillia syndrome (NARES)

• Perennial symptoms, >20% eosinophils on nasal smears

5. Idiopathic/vasomotor

● Tobacco smoke, strong odours, changes in temperature and humidity,

exercise, undetermined

6. Other

Hormonal, food, atrophic

Types of Rhinitis

1. Wallace et al. JACI 2008; 122: S1-84.2. Bousquet et al. ARIA 2008. Allergy 2008; 63 (Sup 86): 8-1603. Kemp et al. Australian Family Physician 2008; 37 (4): 214-220

Department of Allergy and ImmunologyDifferential Diagnosis

1. Nasal polyps

2. Structural/mechanical factors Choanal atresia

Cleft palate

Deviated septum/septal wall defects

Adenoidal hypertrophy

Trauma

Nasal tumors

Foreign body

Pharyngonasal reflux

Acromegaly (excess growth hormone)

3. Cerebospinal fluid rhinorrhoea

4. Ciliary dyskinesia syndrome

Wallace et al. JACI 2008; 122: S1-84.


Allergic rhinitis

1. Background


3. Pathophysiology

4. Classification


6. Investigations

7. Management


1. Holgate ST et al. Treatment strategies for allergy and asthma. Nat Rev

Immunol 2008 Mar;8(3):218-310.


Pathophysiology of AR

1. Immediate response to allergen

Due to mediators of mast cell degranulation

Symptoms – sneezing, watery nose, itch

2. Delayed response to allergen

Due to invasion of inflammatory cells (eosinophils

etc)

Symptoms – as above plus nasal congestion


AR and Asthma

Prevalence

Of patients without rhinitis, asthma prevalence is <2%1

AR independently increases the risk of developing asthma by 2-3 times4,5

Compared to subjects with asthma alone, adults and children with asthma and AR:6-11

Have ↑ asthma-related hospitalisations

Have ↑ GP visits

Incur higher asthma drug costs

Have ↑ absence from work and decreased productivity

1. Bousquet et al. ARIA 2008. Allergy 2008; 63: 8-160

2. Sibblad et al. Thorax 1991; 46: 895-901.

3. Leynaert et al. J Allergy Clin Immunol 1999; 104: 301-4

4. Wright et al. Pediatrics 1994;94:895–901.

5. Settipane et al. Allergy Asthma Proc 2000;21:221-5

6. Bousquet et al. Clin Exp Allergy 2005;35:723–727.

7. Price et al. Clin Exp Allergy 2005;35:282–287.

8. Sazonov Kocevar et al. Allergy 2005;60:338–342.

9. Thomas et al. Pediatrics 2005;115:129–134.

10.Gaugris et al. J Asthma 2006;43:1–7.

11.Sole et al. Pediatr Allergy Immunol 2005;16:121–125.

Allergic rhinitis10-40% have asthma1

Asthma75% have AR 2,3


Allergic rhinitis

1. Background


3. Pathophysiology

4. Classification


6. Investigations

7. Management


Classification 1 of 2

Time of exposure

1. Seasonal (outdoor allergens) Tree pollens: Late winter/early spring

Grass pollens:

Northern coastal areas: Jan/Feb/Mar

Southern coastal areas: Oct/Nov/Dec

Weed pollens: August to May

2. Perennial (indoor allergens) Dust mite, pet dander, moulds, cockroach

3. Occupational

1. Australasian Society of Clinical Immunology and Allergy (ASCIA). www.allergy.org.au

2. Bousquet et al. ARIA 2008. Allergy 2008: 63 (Sup 86): 8-160

http://www.allergy.org.au/


Problems with this classification



Time of exposure

Polysensitised

(majority)

Varies with allergen

exposure

Monosensitised

HDMIntermittent

symptoms

PollensPerennial

symptoms

Non-specific irritants


Intermittent<4 days/week

OR

<4 consecutive weeks/year

Persistent>4 days/week

AND

>4 consecutive weeks/year



ARIA Guidelines

Moderate or Severe(1 or more of below)

1. Sleep disturbance

2. Impairment of daily activities,

leisure and/or sport

3. Impairment of school or work

4. Troublesome symptoms

Mild

1. No sleep disturbance

2. No impairment of daily activities,

leisure and/or sport

3. No impairment of school or work

4. No troublesome symptoms


Allergic rhinitis

1. Background


3. Pathophysiology

4. Classification


6. Investigations

7. Management


History

• Symptom timing &

frequency

Seasonal vs perennial

Days/week, weeks/year

Triggers by pets,

chemicals

• Symptom severity

Troublesome

symptoms

Sleep disturbance

Functional impact on

daytime functioning,

school or work

• Asthma

Nasal symptoms• Sneezing, itchy nose, itchy

palate

• Rhinorrhoea, nasal

obstruction

• Colour: clear, purulent or

blood-tinged

• Unilateral or bilateral

• Mouth breathing,

snoring, nasal voice,

anosmia

Eye symptoms• Intense itching, hyperaemia,

watering, chemosis,

perioribital oedema

Scadding et al. BSACI guidelines for the management of allergic and non-

allergic rhinitis. Clin Exp All 2008;38:19-42.


1. Photo courtesy UpToDate

2. http://www.drrahmatorlummc.com/rhinitisallergy.htm (Accessed

8/4/2013)

http://www.drrahmatorlummc.com/rhinitisallergy.htm


Nose *Pale, oedematous nasal turbinate

mucosa

Excoriation of external nares

Allergic salute

Transverse nasal crease

Eyes Allergic shiners (SC venodilatation)

Dennie-Morgan lines (accentuated folds below lower eyelids)

Mouth High arched palate, mouth breathing

Dental malocclusion

AR - Examination


Allergic rhinitis

1. Background


3. Pathophysiology

4. Classification


6. Investigations

7. Management

Department of Allergy and ImmunologySkin prick testing

Allergen scratched on

back or forearm

Measure wheal at 15

minutes

Average of 2

perpendicular diameters

Result given in millimetres

E.g. 20 mm x 10 mm = 15

mm

Control

Histamine

Negative

1. Australian Society of Clinical Immunology and Allergy (ASCIA) (2008). Skin prick

testing for the diagnosis of allergic disease: A manual for practitioners.

Department of Allergy and ImmunologySPT vs sIgE

SPT sIgE

Minor scratch with itch only

Results visible/compelling

Not affected by antihistamines

Results are instant within 20 minutes Can be performed despite eczema

flare

Most allergens can be tested for,

including fresh food prick testing for

fruits and vegetables

Widely available

Small risk of systemic allergic

reaction

No risk of systemic allergic reaction


Allergic rhinitis

1. Background


3. Pathophysiology

4. Classification


6. Investigations

7. Management


Management of allergic rhinitis

Allergen

avoidance

Pharmaco-

therapy

Immuno-

therapy


● HDM allergen is contained within its body

parts and faecal particles

● Relatively large allergen particle 10-30um

● Remain airborne for short period (20-30 min)

● HDM feed on skin flakes contained within

dust

● Mites infest fabrics (bedding)

● Greatest exposure usually in sleep

1a House dust mite avoidance


Current RCH advice1. HDM encasements – pillow, mattress & doona

2. Remove sheepskin or woollen underlay

3. Remove reservoirs (toys, clothing, furnishings)

4. Remove drapes

5. Every week Wash all bed linen in hot water (>55oC kills HDM)

Vacuum carpet

Damp dust

?Acaricide sprays

?Dehumidifiers & air-filter devices

1a House dust mite avoidance


Sheikh et al. HDM avoidance for perennial allergic rhinitis. 2010

●Only 2 of 7 trials were of good quality (investigated mite impermeable bedding)

● No significant difference between treatment and placebo groups

●Authors’s conclusion

● Acaricide sprays and extensive bedroom based environmental control programmes may be of some benefit in reducing rhinitis symptoms

● HDM impermeable bedding used in isolation is unlikely to be beneficial

HDM avoidance measures

Cochrane Database of Systematic Reviews

Gøtzsche PC, Johansen HK. HDM

avoidance for asthma.

●55 randomised trials and 3121 patients

● Physical methods (n=37)

● Mattress encasings

(n=26)

● Chemical methods (n=10)

● Physical & chemical methods

(n=8)

●Author’s conclusion

● “No effect of the interventions

were found”

● “Chemical and physical methods

aimed at reducing exposure to

HDM allergens cannot be

recommended”


● Criticisms● No subgroup analysis was performed on methods whereby actual

reduction of HDM levels was achieved

● Dust mite reduction achieved in only 17 of 54 trials

● Dust mite reduction unsuccessful in 24 of 54 trials

● Not measured/reported in 13 of 54 trials

● This is relevant given the large range of methods employed to

reduce dust mite

● Physical methods: 16 different methods

● Chemical methods: 6 different methods

1. Kopp et al. Allergy 2009;64:187-188.

Gøtzsche PC, Johansen HK.

House dust mite control measures for asthma.

Cochrane Database of Systematic Reviews 2008, Issue 2.


1. Outdoors Avoid activities with high exposure to pollens

Avoid going outdoors before midday, on windy days or after thunderstorms

Avoid mowing the lawn (wear mask if unavoidable)

Wear sun glasses

Shower after arriving home and irrigate eyes with wet washer

2. Home Keep windows closed

Remove weeds or trees outside the bedroom if particular sensitivities are known.

3. Car Keep windows closed

Use recirculating air-conditioning where possible

Australasian Society of Clinical Immunology and Allergy (ASCIA). www.allergy.org.au

1b Pollen avoidance


● Dogs

● Major allergen: Can f 1

● Principally found in dog’s fur. Also

saliva, skin and urine.

● Cats

● Major allergen: Fel d 1

● Principal source of allergen are

sebaceous glands, saliva and peri-

anal glands

● Fel d 1 is transported in the air by

particles <2.5μm and can remain

airborne for long periods

Bousquet et al. ARIA 2008. Allergy 2008: 63 (Sup 86): 8-160

1c Pet avoidance


1. Bousquet et al. ARIA 2008. Allergy 2008:63(Sup 86):8-160

2. Custovic et al. Allergy 2005; 60: 1112-1115.



Allergen

avoidance

Pharmaco-

therapy

Immuno-

therapy


2. Pharmacotherapy

Intermittent AR

Sneezing, Itching

Minimal drainage

Persistent AR

Congestion, Drainage

+/- Sneezing, Itching

Oral Antihistamine

+/- Saline spray

Nasal Corticosteroid

Antihistamine prn

Nasal Corticosteroid

+ Regular Antihistamine

+ Saline Spray

Immunotherapy

If Mild/Mod/No Asthma


● Mechanism

● Blocks H1 receptor

● Effective against symptoms mediated by histamine

● Rhinorrhoea, sneezing, nasal itching and eye

symptoms

● Less effective against nasal congestion

● Paediatric suspensions● Cetirizine (Zyrtec) >12mo

● Loratidine (Claratyne) >12mo

● Desloratadine (Aerius) > 12mo; >6mo for hives


2a. Antihistamines


Classification of H1-antihistamines

1. Simons FER. Advances in H1-Antihistamines. NEJM

2004;351:2203-17.


1st Generation

H1-Antihistamines

2nd Generation

H1- Antihistamines

Dosing Usually 3-4x/day Usually 1-2x/day

Crossing

BBB

Yes: lipophilicity, low

molecular weight, not

recognised by P-glycoprotein

efflux pump

No: lipophobicity, high molecular

weight, recognised by P-

glycoprotein efflux pump

H receptors

selectivity

Frequently interact with

muscarinic, α-adrenergic and

serotonergic receptors

Highly selective for histamine

receptor

Side effects Potential side effects:

SLUD, sedation, hyperactivity,

insomnia, convulsions

No clinically relevant side effects

DB PC RCT

in children

None Some

Toxicity Case reports are published

regularly

No reports of serious toxicity

Lethality Identified in infants/young

children

Not reported to cause fatality in

overdose

1. de Benedictis et al. New oral H1 antihistamines in children: facts

and unmet needs. Allergy 2008;63:1395-1404.


Death from antihistamines

Clinical presentation overdosage

Adolescents and adults: CNS depression, somonolence and coma

Infants: hallucination, agitation, confusion, convulsion coma

Diphenhydramine OD evidence-based guideline in US

2nd generation antihistamines –no reported deaths with overdose

Medicines and Healthcare product Regulatory Agency (UK)

March 2008: cough & cold medications containing certain ingredients (including 1st generation AH) should not be given to children < 2yo

February 2009: not to be used in children < 6yo

Reported

> 3000 subjects with adverse reactions

Deaths from diphenydramine (n=27) and chlorpheniramine (n=11)

1. Church et al. Allergy 2010;65:459-466


Intranasal Antihistamines

Widely used as first line therapy In USA SAR: Azelastine (Azep) and olopatadine

PAR: Azelastine (Azep)

Potentially advantageous Directly target inflamed mucosa

Faster onset of action

Less side effects

Efficacy Lower NNT compared to oral antihistamines

For congestion, may be better than oral antihistamines, and possibly as effective as intranasal steroids

May potentially have benefit as add-on treatment to intranasal steroids (no further benefit with add-on oral antihistamines)

1. Chipps et al. JACI 2011 (In press)


● Mechanism● Acts by suppressing inflammation at multiple points in

the inflammatory cascade1

● High concentrations can be achieved at the nasal mucosa receptor sites with minimal systemic side effects2

● Efficacy● The most efficacious drug available for both allergic

and non-allergic rhinitis2

● Effective against both nasal congestion and ocular symptoms2

● Meta-analysis shows intranasal steroids are superior to antihistamines3,4

1. Fokkens et al. Am J Rhino 1998; 98: 742-31.


3. Yanez et al. Ann Allergy Asthma Immunol 2002; 89: 479-84

4. Weiner et al. BMJ 1998; 317: 1624-9

2b. Intranasal Steroids


● Over-the-counter● Budesonide (Rhinocort acqueous) 32 mcg

● Fluticasone propionate (Beconase Allergy & Hayfever 24) 50 mcg

● Prescription only● Budesonide (Rhinocort) 64 mcg

● Mometasone (Nasonex) 50 mcg

● Fluticasone furoate (Avamys) 27.5 mcg

● Ciclesonide (Omnaris) 50 mcg

● Onset of action ● 7-8 hours after dosing, but maximum efficacy takes up to 2

weeks

● (Mometasone >) Budesonide > Fluticasone




SteroidAge

(n)

Daily

doseDuration Outcome

Beclomethasone1 6-9 yo

(n=100)336mcg 1 year

Mean change in height was 1cm

lower than placebo (5.0cm vs

5.9cm).

No effect on HPA axis.

Mometasone2 3-9 yo

(n=98)

100mcg

(2 sprays)1 year

No growth suppression.

No effect on HPA axis.

Budesonide3 5-15 yo

(n=78)

256 mcg

(4 sprays)1 year

(n=43)400 mcg

(6 sprays)

6 months

further

Fluticasone4 3.5-9yo

(n=150)

200 mcg

(4 sprays)1 year

1. Skoner et al. Pediatrics 2000;105(2):E23

2. Schenkel et al. Pediatrics 2000;105(2):E22

3. Moller et al. Clin Exp All 2003;33:816-822

4. Allen et al. Allergy Asthma Proc 2002;23(6):407-13.

5. Kemp et al. Australian Family Physician 2008; 37 (4): 214-220

6. Scadding et al. Clin Exp All 2008; 38: 19-42.


Local side effects5,6

Dryness, nasal irritation, sorethroat (10% of users)

Epistaxis due to spraying onto Little’s area – emphasise correct technique


1. Scadding et al. BSACI guidelines for the management of allergic

and non-allergic rhinitis. Clin Exp All 2008; 38: 19-42.



● Saline irrigation1

● Use prior to intranasal corticosteroids

● Useful in clearing mucous and improving ciliary function

● Decongestants (topical/oral) 2,3

Intranasal: Alpha1-agonist (ephedrine) and alpha2-agonist

(xylometazoline) are sympathomimetics that increase nasal

vasoconstriction effective for nasal obstruction in both AR

and non-AR

Oral: Pseudoephedrine weakly effective in reducing nasal

obstruction. Not generally recommended.

Does not improve sneezing, nasal itching or rhinorrhoea

Prolonged use (> 10 days) may lead to tachyphylaxis and

rebound swelling of the nasal mucosa (rhinitis medicaentosa)

1. Kemp et al. Australian Family Physician 2008; 37 (4): 214-220


3. Scadding et al. Clin Exp All. 2008; 38: 19-42.



Does treatment of AR improve asthma

symptoms and control?


Taramarcaz P, Gibson PG. Intranasal corticosteroids for asthma control in

people with coexisting asthma and rhinitis. Cochrane Database of

Systematic Reviews 2003, Issue 3. [SB/DBPCRT]

● 14 SB/DBPRCTs involving 477 subjects

● Meta-analysis did not show statistically significant

benefit

● However, INCS treatment favoured a beneficial

effect on

● Asthma symptom scores

• SMD 0.61, 95% CI -0.04 to 1.26, p=0.07) in 2 parallel studies

● FEV1

• SMD 0.31, 95% CI -0.04 to 0.65, p=0.08) in 5 parallel studies


1. Adapted from Adams et al. JACI 2002; 109:636-42.

2. Adapted from Crystal-Peters et al. JACI 2002; 109:57-62.

Treatment of allergic rhinitis decreases

asthma-related events

Relative risk and incidence density ratio of asthma-related

events (hospitalisation or ED visits) for patients with

asthma who were receiving treatment for allergic rhinitis

*Cetirizine, diphenhydramine, fexofenadine, hydroxyzine, loratadine †Treatment includes INCS and sedating or nonsedating antihistamines


● Leukotriene receptor antagonists1,2

● More effective than placebo, equivalent to oral antihistamines,

but inferior to nasal steroids

● Cromones1,2

● Inhibit the degranulation of sensitised mast cells

● Weakly effective in rhinitis

● Anticholinergics1,2

● Topical ipratropium bromide (Atrovent 21 mcg); needs to be

used 3x/day

● Decreases rhinorrhoea (useful if predominant symptom)


2. Scadding et al. Clin Exp All. 2008; 38: 19-42.

2c. Other medications



Allergen

avoidance

Pharmaco-

therapy

Immuno-

therapy


● What is it?

● First introduced by Noon and Freeman (1911) for

“airborne toxins” using grass-pollen extracts at St

Mary’s Hospital, London1

● Gradual administration of increasing quantities of an

allergen extract to an allergic subject 2

● This ameliorates the symptoms associated with

subsequent exposure to the causative allergen2

1. Noon L. Lancet 1911;i:1572-3


3. Immunotherapy



Immunol 2008 Mar;8(3):218-310.


1. Akdis M et al. Therapuetic manipulation of immune tolerance in allergic

disease. Nat Rev Drug Discov 2009;8(8):645-50.



Immunol 2008 Mar;8(3):218-310.

• ↓ Allergen sIgE

• ↑ Blocking antibodies IgG1, IgG4,IgA

1. ↓ Tissue numbers

2. ↓ Mediator release

• Shift from TH2 TH1

cytokines

• ↑ Treg cells, IL-10 and TGF-

beta

↑IL-10 production


SCIT SLIT

Administration Subcutaneous injections Drops/tablets held for 2 minutes

Setting Doctor’s office Home

Updosing12-16 weeks (weekly

injections)11 days (daily drops)

Maintenance 4-weekly doses 3x/week or daily doses

Cost ~$250-$300/allergen/year ~ $600-$750/allergen/year

Systemic AE 0.05-3.2% of doses1 0.06% of doses

Fatalities 1 in 2-2.5 million doses2-4 None reported

Efficacy

Beneficial for adults with AR

and asthma. Inconclusive for

children (few trials)5-7

Beneficial for AR in adults and

children (recent metanalyses) 8-

10; HDM SLIT not

recommended for children11

3. Immunotherapy

1. Stewart et al. JACI 1992;90:567-568. 2. Reid et al. JACI 1993;92:6-15. 3. Lockey et al. JACI 1987;79:660-677. 4. Bernstein et

al. JACI 2004;113:1129-1136. 5. Caledron et al. Cochrane Database of Systematic Reviews 2007, Issue 1. 6. Abramson et al.

Cochrane Database of Systematic Reviews 2003, Issue 4. 7. Roder et al. Pediatric Allergy and Immunology 2008;19:197-207. 8.

Wilson et al. Cochrane 2003;(2):CD002893. 9. Calamita et al. Allergy 2006;61:1162-72. 10. Penagos et al. Ann Allergy Asthma

Immunol 2006;97:141-8. 11. Brozek et al. JACI 2010;;126:466-766.


● Eligibility

Clinical history of allergy

Documented allergen-

specific sensitisation

Allergen used for

immunotherapy must be

clinically relevant to

clinical history

Poor response to

pharmacotherapy

● Contraindications

● Unstable/severe

asthma

● Concomitant illness

● Pregnancy

● Beta-blocker

treatment

● Poor adherence


3. Immunotherapy

Department of Allergy and ImmunologyImpact on natural history

● Prevention of new sensitisation1

511 patients randomly allocated to SLIT or drugs alone

SLIT given for mites, grass or trees

3 years later, new sensitisations appeared in 38% of controls,

versus 5.9% of SLIT patients (p <0.001)

● Long-lasting effect2

60 children with HDM asthma/rhinitis: 35 SLIT 4-5y, 25 control

SLIT group had significant difference compared to baseline for

presence of asthma (P <0.001), compared to no difference for

control

Difference was present 5 years after SLIT discontinuation

1. Marogna et al. Allergy 2004;59:1205-1210.

2. Di Rienzo et al. Clin Exp Allergy 2003;33:206-210.


Summary

● Allergic rhinitis

Consider allergic and non-allergic causes

Inspect the nose for nasal turbinate oedema

Patients with mild/intermittent AR can be treated

with second generation oral H1-antihistamines

Patients with moderate/severe/persistent AR

should be treated with intranasal corticosteroids

Those who failed treatment should be referred

for consideration of specific allergen

immunotherapy (subcutaneous or sublingual)


Summary

● Asthma

● Majority (75-80%) have rhinitis

● Patients with rhinitis have more frequent asthma

symptoms

● Treatment of rhinitis with intranasal

corticosteroids is likely to benefit asthma control

● Always ask about and optimise rhinitis treatment

in patients with asthma

Department of Allergy and ImmunologyReferral to Allergist Immunologist

1. Medication is ineffective despite 3-6 month trial

or causes adverse reaction.

2. Allergic rhinitis is complicated by a polyp.

3. Allergen desensitization is required.

4. Ongoing symptoms despite optimal topical

nasal corticosteroid therapy and allergen

avoidance.

5. Other severe allergic disease also presents

(e.g. eczema, food allergy, asthma).

6. Refer all children under 3 years old.

http://www.rch.org.au/kidsconnect/clinical.cfm?doc_id=10388

http://www.rch.org.au/kidsconnect/clinical.cfm?doc_id=10388

Allergic Rhinitis and Asthma - Royal Children's Hospital

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