Clinical
Volume 49, Issue 3, March 2020

Long-term management of elderly patients taking immunosuppressive medications

Steven Ivulich    Gregory Snell   
doi: 10.31128/AJGP-10-19-5137   |    Download article
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Background

General practitioners are increasingly likely to encounter elderly patients who are receiving immunosuppressants for the management of autoimmune diseases or solid organ transplants.

Objective

The aim of this article is to provide an overview of the long-term management of the elderly patient treated with immunosuppressants. Recommendations for monitoring, preventing and managing adverse effects of immunosuppressants are summarised.

Discussion

Elderly patients prescribed immunosuppressants may present a number of unique challenges. Immunosenescence, altered pharmacokinetics and the presence of multiple comorbidities can all affect response to immunosuppressants. Through close collaboration with tertiary care providers and regular screening, the general physician is well placed to recognise medication-related complications.

ArticleImage

Elderly patients, generally defined as those aged >65 years, face a number of unique medication-related challenges. The elderly are more likely to have multiple comorbidities and are at increased risk of adverse medication reactions.1 As the population ages, the use of immunosuppressants for the prevention of organ rejection following transplant or for the treatment of autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease is expected to increase. The average age of patients receiving solid organ transplants (SOTs) has increased over the past 20–25 years, and the majority of patients receiving SOTs are now aged >50 years.2 Age is not considered an absolute contraindication to transplant if the elderly recipient has minimal comorbidities. However, frailty is associated with poorer outcomes before and after transplantation.3,4

The management of elderly patients taking immunosuppressants is heavily dependent on close collaboration with tertiary care providers. Regular review at the tertiary institution for short- and long-term complications allows timely adjustment of treatments and early interventions. General practitioners (GPs) are often the primary source of contact for patients, and they may need to manage various aspects of the patients’ care, such as hypertension or diabetes. The GP is therefore ideally placed to recognise medication-related complications (eg adherence difficulties, medication interactions from multiple sources and medication toxicity). Coordinating care with other specialty services will ensure regular screening to recognise complications associated with immunosuppressive therapies.


Immunosenescence

Immunosenescence is a physiological part of ageing typified by an impairment of adaptive and innate immunities.5 Ageing in general has broad consequences for immune responses, organ function, repair mechanisms and metabolic function. Immunosenescence is linked to higher rates of diabetes, bacterial infections and malignancies.5 Immunosenescence may predispose elderly patients to the risks of over-immunosuppression. Theoretically, elderly transplant recipients may benefit from less immunosuppression than younger patients, but further studies are needed.6


Immunosuppressant regimens

The selection of immunosuppressive medication regimens in the elderly is complex as there are no specific guidelines. Specific recommendations for the elderly are difficult to ascertain as the elderly are generally excluded from studies or clinical trials.5 A summary of the available immunosuppressants, medication monitoring and main adverse effects is reported in Table 1. The introduction of biological agents has transformed the treatment of many autoimmune diseases. It is likely that further compounds will be introduced in the future, creating challenges for maintaining up-to-date clinical knowledge required in the monitoring of these highly effective agents.

Table 1. Common immunosuppressants used in the elderly13,23,42–45
Class of medication Generic name Primary care monitoring Main adverse effects
Calcineurin inhibitors Cyclosporin
Tacrolimus
Renal function: Creatinine
Glucose
Electrolytes (potassium, magnesium)
Lipids
Blood pressure
Liver function tests
 
TDM
  • Cyclosporin (C0 and C2 )
  • Tacrolimus (C0 )
  • Levels dependent on indication
Nephrotoxicity
Diabetes (tacrolimus > cyclosporin)
Hypomagnesaemia, hyperkalaemia
Hyperlipidaemia
Hypertension
Neurotoxicity (tacrolimus > cyclosporin) – tremor, headache, confusion, seizures, posterior reversible encephalopathy syndrome, hirsutism, gingival hypertrophy (cyclosporin > tacrolimus)
Mammalian target of rapamycin inhibitors Everolimus
Sirolimus
Renal function: Creatinine
Lipids
Full blood examination
 
TDM
  • Everolimus (C0 )
  • Sirolimus (C0 )
Proteinuria
Hyperlipidaemia
Pancytopenia
Pneumonitis
Peripheral oedema
Delayed wound healing (requires caution prior to major surgeries)
Mouth ulcers
Nucleotide synthesis inhibitors Azathioprine
Mycophenolate
Leflunomide*
Complete blood count
Thiopurine methyltransferase: Azathioprine
Liver function tests
 
TDM
Mycophenolate AUC0-12 may be considered but not universal practice
Dose-related myelosuppression
Pancytopenia, neutropenia
Liver dysfunction
Nausea, diarrhoea
Pneumonitis
 
Corticosteroids Prednisolone Glucose
Lipids
Blood pressure and weight
Bone mineral density
Ophthalmology
Electrolytes
Hyperglycaemia
Hyperlipidaemia
Hypertension/heart failure
Osteopenia
Glaucoma and cataracts
Adrenal suppression
Sleep and mood disturbances
Peptic ulcer disease
Antimetabolites Methotrexate Full blood examination
Liver function tests
Pulmonary function tests
Gastrointestinal
Renal function
Bone marrow suppression
Hepatic fibrosis
Acute interstitial pneumonitis
Nausea, vomiting, stomatitis
Tumor necrosis factor alpha antagonists Adalimumab
Certolizumab
Etanercept
Golimumab
Infliximab
Full blood examination
Tuberculosis and hepatitis B screening
Renal function – creatinine
Liver function tests
 
Neutropenia
Reactivation of hepatitis B
Worsening heart failure
Progressive multifocal leukoencephalopathy
 
Cytokine modulators Abatacept
Anakinra
Baricitinib
Rituximab
Secukinumab
Tocilizumab
Tofacitinib
Ustekinumab
Full blood examination
Tuberculosis and hepatitis B screening
Renal function: Creatinine
Liver function tests
Lipids
Neutropenia, lymphopenia
Reactivation of hepatitis B
Progressive multifocal leukoencephalopathy
Alkylating agents Cyclophosphamide Full blood examination
Midstream urine
Urinalysis
Anaemia, neutropenia
Haemorrhagic cystitis
Heart failure in patients aged >50 years
Pulmonary fibrosis
*Safety profile unchanged in the elderly – monitor for hypertension and unintended weight loss
AUC0–12 , area under the curve concentration; C0 , trough concentration (or lowest concentration) reached before the next dose administered; C2 , concentration taken two hours after receiving dose; TDM, therapeutic drug monitoring

Immunosuppression regimens and protocols are in a constant state of evolution and at present there is no universally agreed consensus to guide therapy. Immunosuppressant doses and serum target levels are individualised according to indication, disease response, side-effect profile, age and frailty of the individual patient. The frequency of monitoring may decrease over time but will reflect the individual patient’s comorbidities and complications.

Therapeutic drug monitoring (TDM) is available for the narrow therapeutic index (NTI) immunosuppressants such as tacrolimus, cyclosporin, everolimus, sirolimus and mycophenolate. However, TDM may not accurately reflect the effects of immunosenescence or the total degree of immunosuppression.7 As a result of immunosenescence, many clinicians may intuitively use lower immunosuppressant doses for elderly patients to minimise the risk of infection and side effects. However, there is no widespread consensus guiding specific TDM of immunosuppressants for the elderly.


Pharmacokinetics of immunosuppressants

In the elderly population, age-related physiological changes can result in clinically significant alterations in the pharmacokinetic parameters of immunosuppressants. The pharmacokinetics of medications, particularly calcineurin inhibitors (CNIs), may be altered in older patients. Initial CNI doses that are similar to those recommended for younger patients may result in higher serum concentrations. A recent study investigating the optimal dosing of CNIs in elderly kidney transplant recipients (aged ≥65 years) found that serum CNI trough levels were 50% higher in the elderly when normalised for dose and weight.8 The reason that elderly patients may require lower doses of CNIs to obtain the same therapeutic levels is because of a reduction in metabolism from CYP3A4 isozymes and reduced P-glycoprotein activity, resulting in improved bioavailability.8

Elderly patients require higher doses of mycophenolic acid (MPA) when compared with younger patients. The reason may be that MPA is strongly bound to serum albumin, and lower albumin levels in elderly patients result in increased clearance of unbound MPA. A pharmacokinetic study comparing MPA exposure in elderly (63 ± 1 years) versus younger (41 ± 5 years) transplant patients showed lower overall exposure and trough concentrations in the elderly.9 Data from liver and renal transplant recipients showed that mycophenolate doses were significantly higher in patients with lower serum albumin when compared with patients who had normal serum albumin.10,11

The metabolism and excretion of methotrexate is affected by age. Elderly patients in particular require close monitoring, as high rates of discontinuation as a result of toxicity have been observed in this cohort of patients.12 Accumulation of methotrexate is likely to lead to side effects such as nausea and vomiting, myelosuppression and liver enzyme elevations.13 Many pharmacokinetic studies of mammalian target of rapamycin (mTOR) inhibitors in the elderly showed no difference with excretion and ageing.14 The effects of ageing on the pharmacokinetics of prednisolone are unknown.15


Generics

Generic substitution of NTI immunosuppressants remains a contentious issue within the transplant community. Bioequivalence studies are performed in healthy young volunteers and do not take into account chronic disease, repeated dosing or medication interactions.16,17 In a prospective single-centre study evaluating a generic formulation of tacrolimus in elderly patients following kidney transplant, the generic product did not meet the bioequivalent standards when compared with the innovator version. The generic formulation had higher trough concentrations and higher exposure.18

Elderly patients receiving CNIs or mycophenolate should consistently receive the same brand of immunosuppressant once they are stabilised. Interchanging brands is likely to result in variability of immunosuppressant levels, potentially exposing the patient to an increased risk of adverse effects.

The introduction of biologics has transformed the treatment of many autoimmune diseases. However, the prohibitive high cost has limited the use of and access to these agents. The lower cost biosimilars are required to be highly similar to the reference product with regard to their clinical efficacy, safety and pharmacokinetics.19 Concerns about immunogenicity when switching from the reference product have limited their widespread uptake. However, clinical trials to date have not shown significant changes in immunogenicity.20


Comorbidities in patients receiving immunosuppressants

Immunosuppressants can cause or exacerbate comorbidities such as hypertension, renal dysfunction, diabetes and hyperlipidaemia.21 Table 2 has a suggested frequency of monitoring for comorbidities or side effects exacerbated by long-term immunosuppression. Even in the absence of immunosuppression, older patients have an increased risk of cardiovascular-related disease or death. Mortality related to cardiovascular disease ranges from 40% after cardiac and renal transplantation, to 20% after liver transplantation, to 5% after lung transplantation.21

Table 2. Management of complications caused by immunosuppressants38,39,42,46–51
System Monitoring Comments
Haematological
 
Myelosuppression
  • Haemoglobin and platelets
  • Full blood count
  • 1–3 monthly
  • 1–3 monthly, suspend likely causative agent if neutrophils <1.5 × 109 cells/L and contact specialist
Lymphoid malignancy
  • No screening guidelines
  • Monitor for signs: fever, weight loss, night sweats, fatigue, swollen lymph nodes
  • Post-transplant lymphoproliferative disorder associated with Epstein–Barr virus mismatch
  • Associated with thioprine use in inflammatory bowel disease
  • Associated with DMARDs for rheumatoid arthritis
  • Routine testing of oncogenic viruses required (Cytomegalovirus, Epstein–Barr virus, Herpes simplex virus)
Cardiovascular* Fasting lipids 6–12 monthly
Diabetes management plan Glycated haemoglobin 3–6 monthly
Blood pressure goals  
Smoking cessation  
Assessment of weight  
Hepatic and renal Liver function tests 1–3 monthly
  Electrolytes, urea, creatinine 1–3 monthly
Respiratory Community-acquired pneumonia Prophylaxis not required
Intravenous therapy may be required
Pneumocystis jirovecii prophylaxis
 
Recommended for:
  • solid organ transplants, active autoimmune disease
  • all patients on equivalent prednisolone 20 mg or higher for two weeks or longer
Treatment of choice: Trimethoprim/sulfamethoxazole
  • duration depends on immunosuppressive regimen
  • continue for six weeks after ceasing prednisolone
Cytomegalovirus pneumonitis Treatment recommended for transplants with specialist advice
Associated with rejection in kidney, lung and heart transplant
Treatment with oral valganciclovir or intravenous ganciclovir
Also covers Cytomegalovirus, Herpes simplex virus, Herpes zoster virus
Gastrointestinal Colonoscopy
 
Refer to National Bowel Cancer Screening Program
Dependent on risk factors
Cytomegalovirus colitis Refer to Respiratory recommendations
Ophthalmology Glaucoma Annually
Cataracts Annually
Cytomegalovirus retinitis Refer to Respiratory recommendations
Musculoskeletal Bone mineral density
 
 
 
Preventive strategies
  • Yearly vitamin D level review
  • Minimise corticosteroid use
  • Antiresorptive therapy as indicated (bisphosphonates or denosumab)
Dental examination for oral hygiene and cancer screening 3–6 monthly
 
Dermatology Dermatological examination
 
Annually
Avoid voriconazole use in patients at risk of skin cancers
Associated with thiopurine use in inflammatory bowel disease
Genitourinary Urinary tract infections
 
Prophylaxis not required
Caution with trimethoprim because it elevates serum creatinine
Avoid nitrofurantoin eGFR <60 mL/minute
Gynaecological examinations
 
Refer to National Cervical Screening Program
Dependent on risk factors (2–5 yearly)
Breast screening Refer to Breast Screen Australia recommendations (two-yearly)
Prostate screening
 
Evidence does not support routine testing
Refer to Prostate Cancer Foundation of Australia Clinical Practice Guidelines
*No current evidence-based guidelines for cardiovascular disease in patients who are taking immunosuppressive medication
DMARD, disease-modifying antirheumatic drug; eGFR, estimated glomerular filtration rate

The most clinically significant change in the elderly is the decline in renal function, with age-related decline in renal function at approximately 10% per decade of increasing age.22 Close monitoring of renal function in the elderly is essential during methotrexate therapy, as many methotrexate-related adverse effects can be related to impaired renal function.12,23 Elderly recipients of lung transplants have higher rates of severe renal dysfunction over long-term follow up than younger receipients of lung transplants.24 CNI minimisation strategies with mTOR inhibitors to preserve renal function may provide benefits in the elderly transplant population.25,26

The risk of developing new-onset diabetes mellitus after transplantation (NODAT) increases 1.5-fold for every decade increase in age following kidney transplant.27 The incidence of NODAT varies across SOT: 4–25% in renal transplant recipients, 2–38% in liver transplant recipients, 7–26% in heart transplant recipients and 32–57% in lung transplant recipients.28–30 Immunosuppressants such as corticosteroids, CNIs and mTOR inhibitors have diabetogenic potential.28 Corticosteroids have the strongest diabetogenic potential, which is dose dependent.


Infectious diseases

Infections are an important cause of morbidity and mortality in elderly patients taking immunosuppressants. Immunocompetence decreases with age, and older patients are more likely to die from bacterial infections than younger transplant recipients. The risk and severity of infection increases with the level of immunosuppression and is usually higher within the first six months after organ transplant.31 SOT recipients aged >50 years have a 2-fold increase in the risk of developing bacteraemia with septic shock.32

The incidence of opportunistic infections – such as Pneumocystis jirovecii (PJP), herpes zoster and tuberculosis – has risen with the increased prescribing of biologics.33 A prospective analysis examined the risk factors for opportunistic infections in patients with inflammatory bowel disease. An increased rate of opportunistic infections was seen in patients aged ≥50 years and with the use of steroids, thiopurines and combination immunosuppressant therapy.34

Immunosuppressive regimens prescribed may predispose to specific infections. For example, corticosteroids predispose to PJP, hepatitis B, bacterial and fungal infections, while T-lymphocyte depletion may activate latent Cytomegalovirus (CMV) reactivation.35,36 Azathioprine has been associated with papillomavirus, and mycophenolate has been associated with late CMV.35

The GP will often be involved in the first-line management of infections in the elderly. The decision to withhold or alter the doses of immunosuppressive therapy should only be undertaken in close consultation with the transplant physician. Although most infectious complications related to immunosuppression are preventable, they can become life threatening in a matter of hours, as infection progresses rapidly in the immunocompromised host. Urgent referral for hospital management is sometimes necessary.

Treatment of infections can be problematic as it may destabilise immunosuppressant regimens as a result of medication interactions and toxicities (eg nephrotoxicity, leukopenias and hepatotoxicity). Table 3 provides a summary of some of the clinically significant medication interactions between immunosuppressants and other frequently prescribed medications in the elderly patient.

Table 3. Clinically significant interactions with immunosuppressants42,49,51–56
Drug class and interaction Comments
Increase CNI and mTOR serum concentrations
Macrolides: Erythromycin, clarithromycin Avoid clarithromycin in Helicobacter pylori eradication therapies
Erythromycin increases CNI level with added potential neurotoxicity
Roxithromycin and azithromycin are safer alternatives
Azole antifungals: Voriconazole, posaconazole, fluconazole, itraconazole
 
Voriconazole and posaconazole are the most potent inhibitors
Fluconazole <150 mg daily has minimal interaction
Dose reduction of 50–67% required at initiation of therapy
Calcium channel blockers: Diltiazem, verapamil
 
Diltiazem has been used to boost CNI levels but is no longer common practice
Nondihydropyridine (amlodipine, nidefipine) reverses the vasoconstriction of CNIs
Decrease CNI serum concentrations
Anti-epileptics: Carbamazepine, phenytoin, phenobarbital Levetiracetam is a safer alternative
Antibacterials: Rifampicin and rifabutin
 
Significant reductions in CNI and mTOR levels
Reduction in mycophenolate and prednisolone exposure
Rifabutin has lower potential but is still significant
Complementary medicines: St John’s wort Enhanced metabolism of CNIs, mTOR inhibitors and prednisolone
Additive nephrotoxicity without changing CNI/mTOR serum concentrations
Non-steroidal anti-inflammatory drugs (including topical) Methotrexate and CNIs
Antibiotics: Trimethoprim-sulfamethoxazole Prophylaxis doses for Pneumocystis jirovecii unlikely to cause nephrotoxicity
Additive bone marrow suppression
Antivirals: Valganciclovir Valaciclovir is a safer alternative: Minimal bone marrow suppression
Antibacterials: Trimethoprim/sulfamethoxazole Methotrexate: Life-threatening pancytopenias
Antiproliferatives: Myophenolate and azathioprine Check TPMT levels prior to initiation of azathioprine
Allopurinol Inhibits metabolism of azathioprine
Other
Statins: Simvastatin amd atorvastatin
 
Cyclosporin increases statin exposure; increases risk of myopathy and rhabdomyolysis
Rosuvastatin and pravastatin are safer alternatives
Colchicine
 
CNIs increase colchicine concentration; start low and monitor for myopathy and gastrointestinal disturbances
Direct-acting oral anticoagulants: Dabigitran Most problematic; concomitant use with cyclosporine is contraindicated
Rivaroxaban Levels increased by cyclosporin with increased risk of bleeding
Apixaban Safest to use with CNIs
Antidepressants SSRIs are weak CYP3A4 inhibitors, but sertraline and escitalopram are agents of choice
CNI, calcineurin inhibitor; CYP, cytochrome enzyme; mTOR, mammalian target of rapamycin; SSRI, selective serotonin reuptake inhibitor; TPMT, thiopurine methyltransferase


Vaccinations

GPs play a crucial part in ensuring that immunisation is up to date. Vaccinating immunocompromised patients can be challenging as they may have a reduced response to vaccines, as well as reduced protection from previous vaccinations. Immunocompromised patients may need extra doses of inactivated vaccines to optimise protection against specific diseases. Vaccination should ideally be undertaken prior to immunosuppressive therapy to improve the immune response.37

Administration of live vaccines – such as measles, mumps and rubella (MMR); varicella and zoster vaccines – to immunocompromised hosts is generally contraindicated. Mildly immunosuppressed patients, such as those taking conventional disease-modifying antirheumatic medications (eg low-dose methotrexate, azathioprine or corticosteroids), can receive live vaccines, but only under rheumatologist advice.37 Otherwise, patients should ideally wait four weeks before starting immunosuppression after receiving a live vaccine.

Table 4 provides an overview of the recommended vaccines for an elderly patient receiving immunosuppressants, and Table 5 provides a list of vaccines that require case-by-case consideration. As recommendations are in a constant state of flux, practitioners are advised to refer to the The Australian immunisation handbook for complete and up-to-date information.

Table 4. Vaccination recommendations for elderly patients prescribed immunosuppressants37
Vaccine Recommended Comments
Influenza All patients aged >65 years
All patients who are immunocompromised
Annually
Ideally at start of influenza season
Higher immunogenic trivalent vaccine recommended
Streptococcus pneumoniae
Pneumococcal conjugate vaccine (13vPCV)
23v pneumococcal polysaccharide vaccine (23vPPV)
All patients aged >65 years
All patients who are immunocompromised
 
Refer to The Australian immunisation handbook
Dosing schedule depends on:
  • Category A (highest risk of pneumococcal disease)
  • previous vaccination status
  • vaccine previously administered
  • pre-existing or newly diagnosed comorbidities
Hepatitis B
 
Patients with specific risk factors:
  • solid organ transplant
  • HSCT
  • HIV
 
Titres required prior to vaccination
If seronegative and never been vaccinated, use standard schedule as accelerated schedule less immunogenic
If have not responded to primary vaccination, give additional doses and remeasure titres
Check immunity annually; if levels fall, give additional boosters
Hepatitis A
 
High-risk patients*
Liver transplant recipients
 
Human papilloma virus
Quadrivalent vaccine
All immunocompromised, all ages Cost may be prohibitive as elderly immunosuppressed patients not included in the National Immunisation Program
Diptheria, tetanus and pertussis
dTpa
 
All patients
 
If no prior vaccination, give standard schedule
Adults aged ≥65 years: Booster dose if last dose >10 years ago
*Chronic hepatitis B or C infection
DMARD, disease-modifying anti-rheumatic drug; HIV, human immunodeficiency virus; HSCT, haematopoietic stem cell transplant
 
Table 5. Vaccines that require case-by-case consideration in immunosuppressed patients
Vaccine Consideration Comments
Zoster Recommended for patients aged >60 years if not immunosuppressed
Consider on a case-by-case basis:
  • patients aged >50 years who are mildly immunocompromised
  • patients with HIV: refer to The Australian immunisation handbook for recommendations
  • patients taking low-dose methotrexate, azathioprine or prednisolone
  • Contraindicated in patients who are significantly immunosuppressed
Serological testing recommended in:
  • patients with HIV
  • patients who will be immunosuppressed in future
 
 
Varicella Consider on a case-by-case basis:
  • patients aged >50 years who are mildly immunocompromised
  • patients taking <20 mg prednisolone equivalent daily.
Contraindicated in patients who are significantly immunosuppressed
Test titres if unknown vaccination history
 
Measles, mumps and rubella (MMR) Consider on a case-by-case basis for patients taking low-dose steroids
Contraindicated in patients who are significantly immunosuppressed
Test titres if unknown vaccination history
 
HIV, human immunodeficiency virus


Malignancy

Immunosenescence may contribute to an increased risk of malignancy in the elderly because of decreased immunosurveillance.5 Cancer incidence and mortality increase after the age of 65 years, levelling off at the age of approximately 85–90 years. The risk for malignancy in transplant recipients is approximately two or three times that seen in the non-transplant population, with the risk related to the intensity and duration of immunosuppression.38

Advanced age has shown to be an important predictor of malignancy in kidney transplant recipients.39 One study reported a five-fold increase in the risk of cancers in kidney transplant recipients aged >60 years when compared with recipients aged <45 years.40 Forty per cent of lung transplant recipients had at least one malignancy at 10 years post-transplantation. The most common cancers are skin related, followed by lymphoproliferative disorders. Recipients aged >65 years had higher rates of skin cancers than younger recipients.24

mTOR inhibitors may have a role in minimising the risk of malignancy because of their dual antiproliferative and anti-cancer activity. mTOR inhibitors can be prescribed for renal cell and breast cancers.41 Although early clinical trials have been promising, evidence to date has not been compelling.38


Conclusion

Age broadly affects the immune response as well as the pharmacokinetics of immunosuppressants. In general, elderly patients are more likely to experience over-immunosuppression, manifesting in infectious complications and malignancy. More studies with older patients are required, as clinical trials have generally excluded the elderly. Close surveillance and collaboration is necessary by all practitioners involved in their care.

Competing interests: None.
Provenance and peer review: Commissioned, externally peer reviewed.
Funding: None.
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GeriatricsImmunosuppressionMultimorbiditiesPharmacotherapy

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