Churg Straus Syndrome – renamed as eosinophilic granulomatosis with polyangiitis (EGPA) – is a specific variant of the group of diseases characterized by necrotizing vasculitis of small and medium-sized systemic blood vessels. Other subtypes within the broad group include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and polyarteritis nodosa. It is distinctive from the other diseases in the category by the coexistence of asthma, rhinosinusitis, and presence of peripheral eosinophilia.
Jacob Churg and Lotte Strauss first described the entity based on autopsy findings in a case series of 13 patients in 1951. They all had a familiar pattern of illness with severe asthma, fever, blood eosinophilia and autopsy evidence of granulomatous necrotizing vasculitis. They named the disease allergic granulomatosis and angiitis. Their classic definition and diagnosis of the disease required presence of all 3 features of:
However, as individuals presented a wide variance of these features, rarely with the presence of all 3 features, more clinically relevant diagnostic criteria became necessary.
Lanham et al. proposed a definition based on:
An unintended drawback of this diagnostic criteria was a delayed diagnosis of the disease waiting until 2 or more organ systems were involved. Early cases with a more favorable prognosis, therefore, ran into the risk of being missed.
American College of Rheumatology proposed new classification criteria in 1990 where 4 out of 6 features needed to be identified:
It rendered a 99.7% specificity and 85% sensitivity for diagnosis.
The Chapel Hill consensus conference in 1994 came up with a definition of EGPA as "eosinophil-rich and granulomatous inflammation involving respiratory tract and necrotizing vasculitis affecting small to medium-sized vessels associated with asthma and eosinophilia."
The significance of this definition was its exclusion of biopsy as a necessity for diagnosis and therefore its ability to recognize early cases with only asthma and tissue and blood eosinophilia.
There have been efforts in recent years to sub-classify clinical phenotypes of eosinophilic granulomatosis with polyangiitis based on the presence or absence of vasculitis, somewhat counterintuitive to the nomenclature itself.
Patients who are ANCA positive (reported around 40% of all EGPA patients) tend to have a vasculitic phenotype and are more common to have myalgia, migrating polyarthralgia, weight loss, mononeuritis multiplex, and renal involvement either as crescentic or necrotizing glomerulonephritis.
Conversely, patients without ANCA positivity tend to have an eosinophilic phenotype with a higher incidence of myocarditis.
Presence of ANCA alone, however, is not the absolute correlate to vasculitis. About 47% of patients in a study by Cottin et al. had vasculitis without seropositivity for ANCA, while 29% were positive for myeloperoxidase ANCA without the presence of vasculitis.
About 41% of patients in the same series by Cottin et al., did not have vasculitis but rather an eosinophilic tissue infiltrate and involvement.
They, therefore, suggested isolating and recognizing a subgroup with features of vasculitis to be defined here.
2. Surrogates of Vasculitis
4. Presence of ANCA
The rest of the patients will fall into the eosinophilic asthma phenotype. It is important to recognize that subgroup early, particularly in the presence of myocarditis with no other evidence of vasculitis. Overly depending on the presence of vasculitis to diagnose EGPA may result in missing out those eosinophilic asthma patients who may otherwise benefit from early targeted therapy.
The primary trigger in pathogenesis in cellular level seems to be an aberrant T-helper cell pathway.
Role of the Th2 Cell Lineage
There have been various theories about what prompts an abnormal Th-2 type immune response in the first place. Allergies, infections, medications have all been considered. The allergy theory has not been substantiated in spite of a high prevalence of IgE levels as studies show that hypersensitivity to currently tested allergens is present only in 30% of cases of CSS. Rolla et al. suggested a superantigen theory in CSS which activated oligoclonal expansion of certain T cell subsets. There has also been some evidence of colonization of airways with Aspergillus or Actinomyces. Several medications have also been reported including sulfonamides, difluinisides, macrolide, and diphenylhydantoin. None of them, however, has been as strong as a possible association between onset of EGPA and use of leukotriene inhibitors montelukast and zafirlukast. Bibby et al. reviewed the USFDA database from 1996 to 2003 to report 181 cases of EGPA in which a pharmacological trigger was suspected. 90% involved leukotriene receptor antagonists. Although some argue that it could merely be the unmasking of disease following ability to wean off steroids in severe asthma after initiation of leukotriene inhibitors.
The pathogenic role of T cells in the aberrant immune response of this disease has been further proven by the presence of specific clonally expanded subpopulations of T cells as well as increased frequency of related HLA alleles like HLA- DRB1 04 and HLA-DRB1 07.
There is an increased serum presence of IL-10 which mediates inhibition of Th-1 response, thus tilting the scale towards differentiation of Th2 cells. This phenomenon is particularly common in ANCA negative phenotype of EGPA.
The estimated prevalence of the disease is 10.7 to 14 per million adults worldwide. Mean age of onset as reported is between 38 to 54 years with a median of 40. However, it has been reported in extremes of age as well, from as low as 4 to as high as 74. There is no gender difference in incidence.
In contrast to certain small vessel vasculitis that has a preponderance in childhood (Henoch-Schonlein purpura, Kawasaki disease), ANCA-associated vasculitis is rare in children. Regardless of age, adult and childhood EGPA both present with highly elevated IgE and eosinophil levels. About 40% of adults have a positive ANCA while 25% of children are seropositive.
Clinically, however, childhood EGPA has a higher incidence of cardiomyopathy, pneumonic infiltrates with a rarer occurrence of mononeuritis multiplex. Higher prevalence of cardiac disease increases the mortality in childhood EGPA, just as in adult disease.
The pathogenesis and clinical phenotype follow a dichotomy of either eosinophil-mediated damage or ANCA-induced endothelial injury.
An initial TH2-mediated immune response provokes the margination of eosinophils. Eosinophilic presence in active disease is likely a consequence of increased synthesis, enhanced extravasation as well as prolonged survival in target tissues. IL-3 and IL-5, produced by TH-2 lymphocytes are the key regulators in maturation and release of eosinophils, as well as their survival in blood. Serum levels of IL-5 correlate consistently with disease activity and go down with the initiation of immunosuppressive therapy.
Epithelial and endothelial cells, when activated by Th-2 type cytokines also secrete eosinophil-specific chemokines like eotaxin 3(CCL26), CCL17, and CCL22. They act on CCR4 receptor to facilitate recruitment of eosinophils and effector Th2 cells to the end organs–thus amplifying the immune response. Martorana et al. demonstrated serum levels of CCL26 as a reliable marker for disease activity in CSS. 
Eosinophils, in turn, release the cationic proteins like eosinophil cationic protein (ECP), eosinophil peroxidases, eosinophil-derived neurotoxins, and eosinophil granule major basic protein which is directly involved in mediating tissue damage.
Eosinophils also secrete cytokines like IL- 1, IL-3, IL-5, TGF- beta, and vascular endothelial growth factor. IL-5, in turn, plays in an active role in maturation, differentiation, and survival of eosinophils.
Histological findings in EGPA are characterized by eosinophilic infiltrates in walls of small and medium-sized blood vessels as well as extravascular tissue spaces. In EGPA with acute pulmonary exacerbations, Bronchoalveolar lavage fluid is also rich in eosinophils, similar to acute or chronic eosinophilic pneumonia. Extravascular eosinophilic granulomas are also observed, particularly in the gastrointestinal tract.
IL- 5 is not the only mediator of eosinophilic tissue infiltration, as has been evidenced by the persistence of tissue Major Basic Protein (MBP) in spite of therapy with mepolizumab causing complete downregulation of IL5 titers. IL-4 and IL-13 are two other potent cytokines of Th-2 profile immune response and may play an important role in tissue infiltration and degranulation of eosinophils.
Elevated p- ANCA levels with” antibodies in a perinuclear pattern are seen in approximately 40% of patients with EGPA. Rarely a cytoplasmic pattern with specificity for neutrophil proteinase 3 (c- ANCA) is seen.
Presence of ANCA correlates with an increased incidence of glomerulonephritis, mononeuritis, and biopsy-proven vasculitis. Alveolar hemorrhage is also found more often in this group of patients.
Infusion of MPO- ANCA in wild-type and Rag2 knockout mice resulted in severe necrotizing and crescentic glomerulonephritis . The 2 subset hypothesis in clinical phenotyping of EGPA has been further substantiated by a recent demonstration of increased frequency of HLA- DRB4 in EGPA patients with ANCA positivity. There has been some recent evidence of the role of Th17 lymphocytes in the occurrence and maintenance of vasculitis response in the disease, particularly with regards to the balance between Th17 and Treg cells.
Clinical features of the disease follow 2-pronged themes of eosinophilic tissue infiltration or small and medium vessel vasculitis.
The clinical course is characterized by 3 phases which do not necessarily always present in the same patient. They may even overlap in the natural history of an individual’s disease.
In the initial prodromal phase, nonspecific symptoms of malaise, fever, migrating polyarthralgia, weight loss is common along with a severe adult-onset form of asthma that is refractory to conventional treatment. Diffuse myalgia and polyarthralgia have been reported in 37% to 57% of CSS patients, particularly at the onset of disease. Upper respiratory symptoms are more common with chronic rhinosinusitis (47% to 93%) and nasal polyps (62% to 77%). However nasal granulomas, erosion, and crusting or epistaxis as seen in GPA are absent here.
The second phase is characterized by eosinophilic infiltrates in end organs along with peripheral eosinophilia. Patchy peripheral nodular pulmonary infiltrates, eosinophilic gastroenteritis, serosal effusion, are common.
An onset of vasculitis characterizes the third phase, and it may take anywhere between 3 to 9 years since the onset of asthma. Neurological symptoms are a hallmark of this phase.
Organ System Involvement
Respiratory and Pulmonary Manifestations
However variable the clinical manifestations may be, Asthma in the prodromal phase seems nearly ubiquitous, reported in 96% to 100% patients. The mean age of onset of asthma is 35 to 50 years, and it precedes the onset of vasculitis by 3 to 9 years.
There has been some debate about certain asthma medications like leukotriene receptor antagonists, montelukast as well as omalizumab precipitating the onset of CSS. However, others believe that they simply help steroid-dependent patients to taper off steroids, thereby unmasking the underlying vasculitides successfully.
Churg-Strauss syndrome patients tend to present with adult-onset asthma with an eosinophilic phenotype. It is accompanied by rhinitis, sinusitis and nasal polyposis more often. Chronic rhinitis is the most common extra thoracic manifestation occurring in about 75% of cases.
Asthma is progressive and often ends up being steroid-dependent asthma. Up to 75% of patients require systemic corticosteroid therapy for asthma control before a diagnosis of EGPA is achieved.
Even when other systemic manifestations of the disease are brought under control with therapy, asthma tends to remain uncontrolled, thus detrimentally affecting the quality of life. Apart from upper airway allergic manifestations and eosinophilic asthma, pulmonary manifestations of the disease can also be related to parenchymal eosinophilic infiltration as well as the vasculitic process. During the first 2 clinical phases described, transient pulmonary infiltrates and eosinophilia is common whereas, in the vasculitic phase, necrotizing vasculitis and granuloma are more common. Alveolar hemorrhage is reported more often in ANCA positive subset although its incidence is lower than in GPA patients.
Cardiac involvement may be present in 62% of cases although it is symptomatically manifest in only 26%. It is caused by both mediators released from activated eosinophils as well as vasculitis lesions in the myocardium and coronary arteries. Myocarditis, in turn, leads to post inflammatory fibrosis and restrictive cardiomyopathy followed by congestive cardiac failure. The spectrum of clinical manifestations varies from coronary artery disease, primary arrhythmias, cardiomyopathy, acute constrictive pericarditis and myocarditis, and eosinophilic pericardial effusion. The absence of ANCA and eosinophilia correlates better with cardiac disease.
Use of echocardiography and cardiac MRI have helped in detecting cardiac abnormalities even beyond an active phase of the disease like nonreversible chronic fibrosis and cardiomyopathy.
Cardiac changes are associated with a poor prognosis and high mortality if left untreated.
Eosinophilic gastroenteritis and mesenteric vasculitis often seem to coincide as far as gastrointestinal tract involvement is concerned. They result in nonspecific symptoms of abdominal pain, nausea, vomiting, and diarrhea to more severe complications like bleeding or intestinal obstruction (mediated by submucosal nodular masses). Mesenteric vasculitis predisposes to ischemic bowel, mucosal ulceration and even perforation necessitating exploratory laparotomy. Serosal involvement can cause eosinophilic ascites and peritonitis. Rare manifestations include necrotizing acalculous cholecystitis, pancreatitis and eosinophilic liver disease.
Renal involvement is seen in 25% of patients and is less common than other medium vessel vasculitides like GPA. The most common manifestation is necrotizing crescentic glomerulonephritis, although focal sclerosing disease, IgA nephropathy or eosinophilic interstitial nephritis can also be seen. The biopsy features are not pathognomonic and often indistinguishable in isolation from other vasculitis diseases, unless combined with the spectrum of eosinophilic asthma, eosinophilia or other system manifestations.
Hypertension is seen in 10% to 30% of patients with EGPA and its presence many reflect the renal involvement.
A wrist or a foot drop resulting from mononeuritis multiplex, or mixed sensorimotor peripheral neuropathy is reported. Common peroneal and internal popliteal nerves are most commonly involved. Radial and ulnar nerves in upper limbs may also be involved. Peripheral neuropathy can be present in 75% to 80% cases. 10% to 39% of neurological involvements can be in the form of CNS vasculitis causing cerebral infarctions or hemorrhages.
Cranial nerve palsies are uncommon but the involvement of cranial nerves 2, 3, 6, and 8 have been described. Ischemic optic neuritis is the most common cranial neuropathy.
Autonomic neuropathies have also been proposed to be the root cause of cardiac dysrhythmia in EGPA patients 
Apart from CNC vasculitis, most neurologic symptoms tend to reverse well to standard therapy.
Dermatological manifestations are present in half to two-thirds of patients.
Extravascular granulomas are seen in the skin as are changes consistent with leukocytoclastic vasculitis. Nonthrombocytopenic palpable purpura is the most common skin manifestation along with scalp nodules, urticarial rashes, skin infarcts, and livedo reticularis.
Among other less common organ system involvements, central retinal artery and venous occlusion, thromboembolic disease, salivary gland involvement or vasculitis involvement of breasts have also been seen.
Because of its protean manifestations, and lack of a single diagnostic test of choice, the diagnosis of EGPA is based on clinical features, more than histopathology or lab testing. With eosinophilic asthma, the clinician must recognize a pattern of multisystem disease and investigate for other supportive findings.
Peripheral blood eosinophilia (greater than 10% on differential white blood cell count or greater than 1500 /dl) is the best-known lab hallmark of the disease. Elevated serum IgE is also found in 75% of patients.
Rest of the laboratory abnormalities are nonspecific including elevated ESR, CRP, normocytic normochromic anemia, and extrapulmonary rheumatoid factor in 60% patients.
As mentioned before, the prevalence of ANCA positivity in EGPA is in approximately 40% of cases. The common ANCA immunofluorescence pattern is perinuclear with specificity for myeloperoxidase (MPO).
Keogh and Specks, in their retrospective study of 74 Churg-Strauss syndrome patients, reported an increased prevalence of neuropathy and central nervous system involvement in ANCA positive patients. There have been increasing efforts since then to identify clinical phenotypes correlating with ANCA positivity. Sable–Fourtassou and colleagues from the French vasculitis study group showed a higher prevalence of renal disease, microliter vasculitis, and peripheral neuropathy in the ANCA positive subgroup of their 112 Churg-Strauss Syndrome patients. Similarly, Sinico and colleagues showed a similar end-organ involvement pattern along with alveolar hemorrhage in the ANCA positive subgroup. In both studies, vasculitis was less frequent in ANCA negative patients, with a higher prevalence of cardiomyopathy and systemic manifestations like malaise, fever, among others.
CT chest shows asymmetric diffuse bilateral peripheral ground glass infiltrates along with bronchial wall thickening. It can sometimes be migratory. Bilateral bronchocentric nodular infiltrates can also occur, but unlike GPA they do not cavitate. Pleural effusion is present in 20% to 30% cases.
CT sinuses are characterized by paranasal sinus thickening along with thickening of nasal mucosa without any evidence of bony erosion (seen in granulomatosis with polyangiitis).
Airflow obstruction is present in pulmonary function test in 70% patients. Even though FEV1 may transiently improve with corticosteroid therapy, airflow obstruction in variable degrees persist in 40% patients.
Since cardiac disease portends a poor prognosis, early detection with cardiac MRI is being advocated even in the absence of clinical symptoms once the disease diagnosis is made. Any patient with suspected EGPA should undergo a thorough evaluation of cardiac performance and coronary status.
Sural nerve biopsy is the gold standard test in documenting peripheral neuropathy. Evidence of axonal degeneration is the most common finding, and necrotizing vasculitis and perineural eosinophilic infiltration can only be confirmed in half of the cases.
Skin biopsy is the most convenient to perform. Although none of the findings are exclusive to EGPA, evidence of small vessel vasculitis in an appropriate clinical setting may be enough to clinch a diagnosis. If the kidney is involved and biopsied, focal necrosis, crescentic deposits, and the paucity of immunoglobulin deposits are the characteristic findings.
Early recognition and ability to use corticosteroids and immunosuppressants have significantly changed the natural history of EGPA, improving prognosis and overall survival.
Corticosteroids help in reduction of eosinophil burden in blood and tissues and inhibit the prolongation of eosinophil survival in extravascular tissues.
While the initial dose of therapy for a non-severe disease has been 1 mg/kbw of oral prednisone, induction of remission in severe disease is often better achieved with pulse dose methylprednisolone with or without cyclophosphamide.
Two randomized controlled trials by the French vasculitis study group established a standardized regimen of treatment based on a 5-factor score. In patients without poor prognostic factors, corticosteroid alone was able to achieve remission in 93% of patients. However, relapses happened more commonly and during tapering of steroids prompting the addition of cyclophosphamide or azathioprine for maintenance. There is an overview of the treatment plan based on a study by Ribi et al. below.
Multiple studies show that maintaining remission with a high incidence of relapses is challenging. Although agents of choice have been well established, the ideal duration of treatment and which drugs to stop first are still not well standardized.
Treatment strategy for frequent relapse or severe refractory disease somewhat depends on end-organ involvement.
Plasmapheresis is effective and preferred in rapidly progressive glomerulonephritis or alveolar hemorrhage.
Intravenous immunoglobulin, on the other hand, is considered in neuropathy or cardiomyopathy refractory to conventional therapy.
Based on smaller case series and well-evidenced success with other ANCA-associated vasculitis, rituximab (anti CD 20) and tumor necrosis factor inhibitors (TNF) are considered as an alternate option.
There has also been some success with interferon-alfa (3 million IU 3 times weekly subcutaneously) for induction of remission in seven CSS patients refractory to cyclophosphamide. It down-regulates expression of IL-5 (known to have an increased titer in CSS) and IL-13, apart from modulating eosinophil activating cytokines in CSS. However, it was unable to reduce the rate of relapses after one year of follow-up.
There have also been recent reports of successful use of mepolizumab–an anti-IL-5 monoclonal antibody as well as omalizumab (recombinant humanized monoclonal anti-IVIG E antibody) in refractory EGPA. Both drugs have already been in use for moderate to severe persistent asthma with allergic phenotypes.
The challenge as evident in multiple studies is to maintain remission with a high incidence of relapses. Although agents of choice have been well established, the ideal duration of treatment, and which drugs to stop first is still not well standardized.
Treatment Strategies for Eosinophilic Granulomatosis with Polyangiitis
Induction of Remission
Without Poor Prognosis (FFS greater than 1)
With Poor Prognosis
Maintenance of Remission
Conditions that need to be considered in the differential stems from the 2 principal phenotypes of EGPA – eosinophilic lung disease and systemic small and medium vessel vasculitis.
Eosinophilic Lung Diseases
Small and Medium Vessel Vasculitis
Most of the eosinophilic lung diseases are distinguished from EGPA by lack of multisystem involvement except Idiopathic hypereosinophilic syndrome where peripheral eosinophilia more than 1500/ cubic mm is a chronic phenomenon lasting beyond 6 months. ANCA is completely absent in hypereosinophilic syndrome, and late-onset asthma is very uncommon. Recent molecular genetic testing has helped in identifying mutations specific to idiopathic hypereosinophilic syndromes, for example, FIP1-like 1-platelet-derived growth factor receptor–alpha or T-cell antigen receptor rearrangements.
As far as differentiation from other small and medium vessel vasculitides is concerned, renal involvement is much more common in granulomatosis with polyangiitis (GPA) as is evidence of cavitary lung lesions or necrotizing upper airway lesions. Septal nasal perforation often reported in GPA does not occur in EGPA.
Following timely detection and treatment, CSS has a favorable prognosis with a 5-year survival of 90%.
Relapse rate is estimated at approximately 20% to 30% and is often minor with fever, joint pain and constitutional symptoms.
Certain risk factors for relapse include:
Just as peripheral eosinophilia is a hallmark of diagnosis, there is an association between the degree of eosinophilia and extent of vasculitis disease. A sudden rise in eosinophil count also precedes a relapse of vasculitis.
They became the basis of the Five Factor Score (FFS) used to define a poor prognosis and higher mortality in EGPA. The absence of any of the five factors carries a good prognosis (RR 0.52; 95% CI, 0.42 to 0.62; P < .03) and the presence of 2 or more increases the risk of mortality (RR 1.36; 95% CI, 1.10 to 1.62; P < .001). Of the 5 factors, cardiomyopathy is an independent risk factor in CSS (hazard ratio 3.39; 95% CI, 1.6 to 7.3).
The Birmingham Vasculitis Activity Score (BVAS) is a detailed 66 question tool to assess vasculitic organ involvement and is widely used in clinical trials.
Vasculitis Damage Index (VDI) assesses accumulated organ damage and is a very useful assessment of organ injury due to both disease itself and its treatment. It correlates well with mortality and morbidity.
Cardiac involvement is the most frequent cause of mortality in patients with poor response to therapy.
Even though the disease has a favorable prognosis with early detection and treatment, asthma often remains refractory and impacts the quality of life (3). Persistence of severe asthma symptoms often necessitates a much longer course of systemic corticosteroids compared to other small vessel vasculitides. As reported by Solans et al., there is, therefore, an expected high prevalence of corticosteroid-induced side effects including diabetes mellitus, myopathy, osteoporosis, and vertebral fractures, osteonecrosis of femoral head etc.
Moreover, almost all patients with EGPA develop long-lasting steroid refractory neuralgia and myopathy as well.
Eosinophilic granulomatosis with Polyangiitis, previously known as Churg-Strauss Syndrome is a multisystem disease of the immune system.
Poorly controlled Asthma over months with sinus and nasal symptoms, particularly when associated with high blood eosinophil count should prompt a red flag to search for this possibility.
Early initiation of treatment with steroids and other immunosuppressants usually leads to a favorable outcome and long life expectancy
Bronchial asthma, and some muscle and nerve weakness may remain lifelong
Careful periodic screening for corticosteroid-induced adverse effects become essential as the disease may require long-term treatment with high-dose steroids over months.
Compliance with the diagnostic procedures and treatment recommendations is essential and therefore regular follow up with the healthcare provider should not be ignored once the disease is diagnosed.
Churg-Strauss Syndrome or Eosinophilic Granulomatosis with Polyangiitis is thus a pleiotropic systemic vasculitis with a dual face of manifestations- based on eosinophilic damage or ANCA associated small and medium vessel injury.
The dichotomy has made it challenging to identify a gold standard for diagnosis and has also made prognosis somewhat variable. Pharmacologic treatment, irrespective of a mechanism of injury, is still tied to early recognition, and treatment with immunomodulators with use of plasma exchange or IVIG is reserved for more refractory cases.
It responds well to treatment but is also characterized by a high remission rate and a lingering persistence of difficult to control asthma and systemic manifestations affecting quality of life
In the era of cost curtailment in healthcare and broadening of first access to healthcare in independent urgent care centers (as opposed to multispecialty hospital emergency rooms), it is important to be aware of the exceptions to the Occam’s razor principle.
When an asthmatic returns for exacerbations time and again in spite of conventional therapy, it is important to recognize the pattern of recurrence or persistence. Broadening the suspicion and correlating with simple initial blood work like cell differential, ESR, CRP, and even IgE is worthwhile. Other organ involvement like cardiomyopathy, renal disease, or GI symptoms, if present, should be tied together to a common unified diagnosis like EGPA. In a patient with eosinophilic asthma and multisystem involvement, discontinuation of leukotriene receptor antagonists should also be considered due to their potential role in pathogenesis. Prompt recognition and treatment are not only rewarding to the healthcare provider but immensely impactful to the prognosis and life expectancy in diseases like EGPA.
Finally, post diagnosis and treatment, awareness of a likelihood of prolonged steroid dependence and therefore its adverse effects becomes essential. Periodic screening of glycemic status, bone density, fall prevention, and infection prevention becomes a routine care plan for the disease.
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