Pathogenesis, Clinical features, Diagnosis, and Management of Community Acquired Pneumonia

 INTRODUCTION:

Community-acquired pneumonia (CAP) is a leading cause of morbidity and mortality worldwide. The clinical presentation of CAP varies, ranging from mild pneumonia characterized by fever and productive cough to severe pneumonia characterized by respiratory distress and sepsis. Because of the wide spectrum of associated clinical features, CAP is a part of the differential diagnosis of nearly all respiratory illnesses.

DEFINITIONS:

Community-acquired pneumonia (CAP) refers to an acute infection of the pulmonary parenchyma acquired outside of the hospital.

●Nosocomial pneumonia refers to an acute infection of the pulmonary parenchyma acquired in hospital settings and encompasses both hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP).

•HAP refers to pneumonia acquired ≥48 hours after hospital admission.

•VAP refers to pneumonia acquired ≥48 hours after endotracheal intubation.

Risk factors:

Older age – The risk of CAP rises with age. The annual incidence of hospitalization for CAP among adults ≥65 years old is approximately 2000 per 100,000 in the United States. This figure is approximately three times higher than the general population and indicates that 2 percent of the older adult population will be hospitalized for CAP annually .

Chronic comorbidities – The comorbidity that places patients at highest risk for CAP hospitalization is chronic obstructive pulmonary disease (COPD), with an annual incidence of 5832 per 100,000 in the United States [7]. Other comorbidities associated with an increased incidence of CAP include other forms of chronic lung disease (eg, bronchiectasis, asthma), chronic heart disease (particularly congestive heart failure), stroke, diabetes mellitus, malnutrition, and immunocompromising conditions.

Viral respiratory tract infection – Viral respiratory tract infections can lead to primary viral pneumonias and also predispose to secondary bacterial pneumonia. This is most pronounced for influenza virus infection.

Impaired airway protection – Conditions that increase risk of macroaspiration of stomach contents and/or microaspiration of upper airway secretions predispose to CAP, such as alteration in consciousness (eg, due to stroke, seizure, anesthesia, drug or alcohol use) or dysphagia due to esophageal lesions or dysmotility.

Smoking and alcohol overuse – Smoking, alcohol overuse (eg, >80 g/day), and opioid use are key modifiable behavioral risk factors for CAP.

Other lifestyle factors – Other factors that have been associated with an increased risk of CAP include crowded living conditions (eg, prisons, homeless shelters), residence in low-income settings, and exposure to environmental toxins (eg, solvents, paints, or gasoline).

MICROBIOLOGY:

Common causes — Streptococcus pneumoniae (pneumococcus) and respiratory viruses are the most frequently detected pathogens in patients with CAP.

The most commonly identified causes of CAP can be grouped into three categories:

●Typical bacteria

•S. pneumoniae (most common bacterial cause)

•Haemophilus influenzae

•Moraxella catarrhalis

•Staphylococcus aureus

•Group A streptococci

•Aerobic gram-negative bacteria (eg, Enterobacteriaceae such as Klebsiella spp or Escherichia coli)

•Microaerophilic bacteria and anaerobes (associated with aspiration)

●Atypical bacteria ("atypical" refers to the intrinsic resistance of these organisms to beta-lactams and their inability to be visualized on Gram stain or cultured using traditional techniques)

•Legionella spp

•Mycoplasma pneumoniae

•Chlamydia pneumoniae

•Chlamydia psittaci

•Coxiella burnetii

●Respiratory viruses

•Influenza A and B viruses

•Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

•Other coronaviruses (eg, CoV-229E, CoV-NL63, CoV-OC43, CoV-HKU1)

•Rhinoviruses

•Parainfluenza viruses

•Adenoviruses

•Respiratory syncytial virus

•Human metapneumovirus

•Human bocaviruses

PATHOGENESIS:

CAP has been viewed as an infection of the lung parenchyma, primarily caused by bacterial or viral respiratory pathogens. In this model, respiratory pathogens are transmitted from person to person via droplets or, less commonly, via aerosol inhalation (eg, as with Legionella or Coxiella species). Following inhalation, the pathogen colonizes the nasopharynx and then reaches the lung alveoli via microaspiration. When the inoculum size is sufficient and/or host immune defenses are impaired, infection results. Replication of the pathogen, the production of virulence factors, and the host immune response lead to inflammation and damage of the lung parenchyma, resulting in pneumonia (figure 3).

With the identification of the lung microbiome, that model has changed [19-21]. While the pathogenesis of pneumonia may still involve the introduction of respiratory pathogens into the alveoli, the infecting pathogen likely has to compete with resident microbes to replicate. In addition, resident microbes may also influence or modulate the host immune response to the infecting pathogen. If this is correct, an altered alveolar microbiome (alveolar dysbiosis) may be a predisposing factor for the development of pneumonia.

In some cases, CAP might also arise from uncontrolled replication of microbes that normally reside in the alveoli. The alveolar microbiome is similar to oral flora and is primarily comprised of anaerobic bacteria (eg, Prevotella and Veillonella) and microaerophilic streptococci. Hypothetically, exogenous insults such as a viral infection or smoke exposure might alter the composition of the alveolar microbiome and trigger overgrowth of certain microbes. Because organisms that compose the alveolar microbiome typically cannot be cultivated using standard cultures, this hypothesis might explain the low rate of pathogen detection among patients with CAP.

In any scenario, the host immune response to microbial replication within the alveoli plays an important role in determining disease severity. For some patients, a local inflammatory response within the lung predominates and may be sufficient for controlling infection. In others, a systemic response is necessary to control infection and to prevent spread or complications, such as bacteremia. In a minority, the systemic response can become dysregulated, leading to tissue injury, sepsis, acute respiratory distress syndrome, and/or multiorgan dysfunction.

CLINICAL PRESENTATION:

The clinical presentation of CAP varies widely, ranging from mild pneumonia characterized by fever, cough, and shortness of breath to severe pneumonia characterized by sepsis and respiratory distress. Symptom severity is directly related to the intensity of the local and systemic immune response in each patient.

●Pulmonary signs and symptoms – Cough (with or without sputum production), dyspnea, and pleuritic chest pain are among the most common symptoms associated with CAP. Signs of pneumonia on physical examination include tachypnea, increased work of breathing, and adventitious breath sounds, including rales/crackles and rhonchi. Tactile fremitus, egophony, and dullness to percussion also suggest pneumonia. These signs and symptoms result from the accumulation of white blood cells (WBCs), fluid, and proteins in the alveolar space. Hypoxemia can result from the subsequent impairment of alveolar gas exchange. On chest radiograph, accumulation of WBCs and fluid within the alveoli appears as pulmonary opacities.

●Systemic signs and symptoms – The great majority of patients with CAP present with fever. Other systemic symptoms such as chills, fatigue, malaise, chest pain (which may be pleuritic), and anorexia are also common. Tachycardia, leukocytosis with a leftward shift, or leukopenia are also findings that are mediated by the systemic inflammatory response. Inflammatory markers, such as the erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and procalcitonin may rise, though the latter is largely specific to bacterial infections. CAP is also the leading cause of sepsis; thus, the initial presentation may be characterized by hypotension, altered mental status, and other signs of organ dysfunction such as renal dysfunction, liver dysfunction, and/or thrombocytopenia.

Diagnosis:

A chest X-ray looks for inflammation in your lungs. A chest X-ray is often used to diagnose pneumonia.

Blood tests, such as a complete blood count (CBC) see whether your immune system is fighting an infection.

Pulse oximetry measures how much oxygen is in your blood. Pneumonia can keep your lungs from getting enough oxygen into your blood. To measure the levels, a small sensor called a pulse oximeter is attached to your finger or ear.

A blood gas test may be done if you are very sick. For this test, your provider measures your blood oxygen levels using a blood sample from an artery, usually in your wrist. This is called an arterial blood gas test.

A sputum test, using a sample of sputum (spit) or mucus from your cough, may be used to find out what germ is causing your pneumonia.

A blood culture test can identify the germ causing your pneumonia and also show whether a bacterial infection has spread to your blood.

A polymerase chain reaction (PCR) test quickly checks your blood or sputum sample to find the DNA of germs that cause pneumonia.

A bronchoscopy looks inside your airways. If your treatment is not working well, this procedure may be needed. At the same time, your doctor may also collect samples of your lung tissue and fluid from your lungs to help find the cause of your pneumonia.

A chest computed tomography (CT) scan can show how much of your lungs are affected by pneumonia. It can also show whether you have complications such as lung abscesses or pleural disorders. A CT scan shows more detail than a chest X-ray.

A pleural fluid culture can be taken using a procedure called thoracentesis, which is when a doctor uses a needle to take a sample of fluid from the pleural space between your lungs and chest wall. The fluid is then tested for bacteria.

DIFFERENTIAL DIAGNOSIS:

Congestive heart failure with pulmonary edema

•Pulmonary embolism

•Pulmonary hemorrhage

•Atelectasis

•Aspiration or chemical pneumonitis

•Drug reactions

•Lung cancer

•Collagen vascular diseases

•Vasculitis

•Acute exacerbation of bronchiectasis

•Interstitial lung diseases (eg, sarcoidosis, asbestosis, hypersensitivity pneumonitis, cryptogenic organizing pneumonia)

TREATMENT:

Outpatient antibiotic therapy:

For most patients aged <65 years who are otherwise healthy and have not recently used antibiotics, we typically use oral amoxicillin (1 g three times daily) plus a macrolide (eg, azithromycin or clarithromycin) or doxycycline. Generally, we prefer to use a macrolide over doxycycline.

This approach differs from the American Thoracic Society (ATS)/Infectious Diseases Society of America (IDSA), which recommend monotherapy with amoxicillin as first line and monotherapy with either doxycycline or a macrolide (if local resistance rates are <25 percent [eg, not in the United States]) as alternatives for this population [26]. The rationale for each approach is discussed separately. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting", section on 'Empiric antibiotic treatment'.)

●For patients who have major comorbidities (eg, chronic heart, lung, kidney, or liver disease, diabetes mellitus, alcohol dependence, or immunosuppression), who are smokers, and/or who have used antibiotics within the past three months, we suggest oral amoxicillin-clavulanate (875 mg twice daily or extended release 2 g twice daily) plus either a macrolide (preferred) or doxycycline.

Inpatient antibiotic therapy:

For patients without suspicion for MRSA or Pseudomonas, we generally use one of two regimens: combination therapy with a beta-lactam plus a macrolide or monotherapy with a respiratory fluoroquinolone. Because these two regimens have similar clinical efficacy, we select among them based on other factors (eg, antibiotic allergy, drug interactions). For patients who are unable to use either a macrolide or a fluoroquinolone, we use a beta-lactam plus doxycycline.

●For patients with known colonization or prior infection with Pseudomonas, recent hospitalization with IV antibiotic use, or other strong suspicion for pseudomonal infection, we typically use combination therapy with both an antipseudomonal beta-lactam (eg, piperacillin-tazobactam, cefepime, ceftazidime, meropenem, or imipenem) plus an antipseudomonal fluoroquinolone (eg, ciprofloxacin or levofloxacin). The selection of empiric regimens should also be informed by the susceptibility pattern for prior isolates.

●For patients with known colonization or prior infection with MRSA or other strong suspicion for MRSA infection, we add an agent with anti-MRSA activity, such as vancomycin or linezolid, to either of the above regimens. We generally prefer linezolid over vancomycin when community-acquired MRSA is suspected (eg, a young, otherwise healthy patient who plays contact sports presenting with necrotizing pneumonia) because of linezolid's ability to inhibit bacterial toxin production.Ceftaroline is a potential alternative for the treatment of MRSA pneumonia but is not US Food and Drug Administration approved.

PREVENTION:

The three primary pillars for the prevention of CAP are:

●Smoking cessation (when appropriate)

●Influenza vaccination for all patients

●Pneumococcal vaccination for at-risk patients

Diabetes Mellitus

 Introduction of Diabetes:

Diabetes mellitus is taken from the Greek word diabetes, meaning siphon - to pass through and the Latin word mellitus meaning sweet.

Diabetes mellitus (DM) is a metabolic disease, involving inappropriately elevated blood glucose levels. DM has several categories, including type 1, type 2, maturity-onset diabetes of the young (MODY), gestational diabetes, neonatal diabetes, and secondary causes due to endocrinopathies, steroid use, etc. The main subtypes of DM are Type 1 diabetes mellitus (T1DM) and Type 2 diabetes mellitus (T2DM), which classically result from defective insulin secretion (T1DM) and/or action (T2DM). T1DM presents in children or adolescents, while T2DM is thought to affect middle-aged and older adults who have prolonged hyperglycemia due to poor lifestyle and dietary choices. The pathogenesis for T1DM and T2DM is drastically different, and therefore each type has various etiologies, presentations, and treatments.

Etiology of Diabetes:

In the islets of Langerhans in the pancreas, there are two main subclasses of endocrine cells: insulin-producing beta cells and glucagon secreting alpha cells. Beta and alpha cells are continually changing their levels of hormone secretions based on the glucose environment. Without the balance between insulin and glucagon, the glucose levels become inappropriately skewed. In the case of DM, insulin is either absent and/or has impaired action (insulin resistance), and thus leads to hyperglycemia.

Type 1 Diabetes Mellitus:

T1DM is characterized by the destruction of beta cells in the pancreas, typically secondary to an autoimmune process. The result is the absolute destruction of beta cells, and consequentially, insulin is absent or extremely low.

Type 2 Diabetes Mellitus:

T2DM involves a more insidious onset where an imbalance between insulin levels and insulin sensitivity causes a functional deficit of insulin. Insulin resistance is multifactorial but commonly develops from obesity and aging.

The genetic background for both types is critical as a risk factor. As the human genome gets further explored, there are different loci found that confer risk for DM. Polymorphisms have been known to influence the risk for T1DM, including major histocompatibility complex (MHC) and human leukocyte antigen (HLA).

T2DM involves a more complex interplay between genetics and lifestyle. There is clear evidence suggesting that T2DM is has a stronger hereditary profile as compared to T1DM. The majority of patients with the disease have at least one parent with T2DM.

Monozygotic twins with one affected twin have a 90% likelihood of the other twin developing T2DM in his/her lifetime.[3] Approximately 50 polymorphisms to date have been described to contribute to the risk or protection for T2DM. These genes encode for proteins involved in various pathways leading to DM, including pancreatic development, insulin synthesis, secretion, and development, amyloid deposition in beta cells, insulin resistance, and impaired gluconeogenesis regulation. A genome-wide association study (GWAS) found genetic loci for transcription factor 7-like 2 gene (TCF7L2), which increases the risk for T2DM.[4][5] Other loci that have implications in the development of T2DM include NOTCH2, JAZF1, KCNQ1, and WFS1.

Maturity-onset diabetes of the young (MODY):

MODY is a heterogeneous disorder identified by non-insulin-dependent diabetes diagnosed at a young age (usually under 25 years). It carries an autosomal dominant transmission and does not involve autoantibodies as in T1DM. Several genes have implications in this disease, including mutations to hepatocyte nuclear factor-1-alpha (HNF1A) and the glucokinase (GCK) gene, which occurs in 52 to 65 and 15 to 32 percent of MODY cases, respectively.[8][9] The genetics of this disease are still unclear as some patients have mutations but never develop the disease, and others will develop clinical symptoms of MODY but have no identifiable mutation.

Gestational diabetes:

Gestational diabetes is essentially diabetes that manifests during pregnancy. It is still unknown why it develops; however, some speculate that HLA antigens may play a role, specifically HLA DR2, 3, and 4. Excessive proinsulin is also thought to play a role in gestational diabetes, and some suggest that proinsulin may induce beta-cell stress. Others believe that high concentrations of hormones such as progesterone, cortisol, prolactin, human placental lactogen, and estrogen may affect beta-cell function and peripheral insulin sensitivity.

Several endocrinopathies, including acromegaly, Cushing syndrome, glucagonoma, hyperthyroidism, hyperaldosteronism, and somatostatinomas, have been associated with glucose intolerance and diabetes mellitus, due to the inherent glucogenic action of the endogenous hormones excessively secreted in these conditions. Conditions like idiopathic hemochromatosis are associated with diabetes mellitus due to excessive iron deposition in the pancreas and the destruction of the beta cells.

Pathophysiology:

A patient with DM has the potential for hyperglycemia. The pathology of DM can be unclear since several factors can often contribute to the disease. Hyperglycemia alone can impair pancreatic beta-cell function and contributes to impaired insulin secretion. Consequentially, there is a vicious cycle of hyperglycemia leading to an impaired metabolic state. Blood glucose levels above 180 mg/dL are often considered hyperglycemic in this context, though because of the variety of mechanisms, there is no clear cutoff point. Patients experience osmotic diuresis due to saturation of the glucose transporters in the nephron at higher blood glucose levels. Although the effect is variable, serum glucose levels above 250 mg/dL are likely to cause symptoms of polyuria and polydipsia.

Insulin resistance is attributable to excess fatty acids and proinflammatory cytokines, which leads to impaired glucose transport and increases fat breakdown. Since there is an inadequate response or production of insulin, the body responds by inappropriately increasing glucagon, thus further contributing to hyperglycemia. While insulin resistance is a component of T2DM, the full extent of the disease results when the patient has inadequate production of insulin to compensate for their insulin resistance. 

Chronic hyperglycemia also causes nonenzymatic glycation of proteins and lipids. The extent of this is measurable via the glycation hemoglobin (HbA1c) test. Glycation leads to damage in small blood vessels in the retina, kidney, and peripheral nerves. Higher glucose levels hasten the process. This damage leads to the classic diabetic complications of diabetic retinopathy, nephropathy, and neuropathy and the preventable outcomes of blindness, dialysis, and amputation, respectively.

History and Physical:

During patient history, questions about family history, autoimmune diseases, and insulin-resistant are critical to making the diagnosis of DM. It often presents asymptomatically, but when symptoms develop, patients usually present with polyuria, polydipsia, and weight loss. On physical examination of someone with hyperglycemia, poor skin turgor (from dehydration) and a distinctive fruity odor of their breath (in patients with ketosis) may be present. In the setting of diabetic ketoacidosis (DKA), clinicians may note Kussmaul respirations, fatigue, nausea, and vomiting. 

Funduscopic examination in a patient with DM may show hemorrhages or exudates on the macula. In frank diabetic retinopathy, retinal venules may appear dilated or occluded. The proliferation of new blood vessels is also a concern for ophthalmologists and can hasten retinal hemorrhages and macular edema, ultimately resulting in blindness. While T1DM and T2DM can present similarly, they can be distinguished based on clinical history and examination. T2DM patients are typically overweight/obese and present with signs of insulin resistance, including acanthosis nigricans, which are hyperpigmented, velvety patches on the skin of the neck, axillary, or inguinal folds. Patients with a longer course of hyperglycemia may have blurry vision, frequent yeast infections, numbness, or neuropathic pain. The clinicians must ask the patient bout any recent skin changes in their feet during each visit. The diabetic foot exam, including the monofilament test, should be a part of the routine physical exam.

Evaluation:

The diagnosis of T1DM is usually through a characteristic history supported by elevated serum glucose levels (fasting glucose greater than 126 mg/dL, random glucose over 200 mg/dL, or hemoglobin A1C (HbA1c exceeding 6.5%) with or without antibodies to glutamic acid decarboxylase (GAD) and insulin.

Fasting glucose levels and HbA1c testing are useful for the early identification of T2DM. If borderline, a glucose tolerance test is an option to evaluate both fasting glucose levels and serum response to an oral glucose tolerance test (OGTT). Prediabetes, which often precedes T2DM, presents with a fasting blood glucose level of 100 to 125 mg/dL or a 2-hour post-oral glucose tolerance test (post-OGTT) glucose level of 140 to 200 mg/dL.

According to the American Diabetes Association (ADA), a diagnosis of diabetes is through any of the following: An HbA1c level of 6.5% or higher; A fasting plasma glucose level of 126 mg/dL (7.0 mmol/L) or higher (no caloric intake for at least 8 hours); A two-hour plasma glucose level of 11.1 mmol/L or 200 mg/dL or higher during a 75-g OGTT; A random plasma glucose of 11.1 mmol/L or 200 mg/dL or higher in a patient with symptoms of hyperglycemia (polyuria, polydipsia, polyphagia, weight loss) or hyperglycemic crisis.[24] The ADA recommends screening adults aged 45 years and older regardless of risk, while the United States Preventative Service Task Force suggests screening individuals between 40 to 70 years who are overweight.

To test for gestational diabetes, all pregnant patients have screening between 24 to 28 weeks of gestation with a 1-hour fasting glucose challenge test. If blood glucose levels are over 140mg/dL, patients have a 3-hour fasting glucose challenge test to confirm a diagnosis. A positive 3-hours OGTT test is when there is at least one abnormal value (greater than or equal to 180, 155, and 140 mg/dL for fasting one-hour, two-hour, and 3-hour plasma glucose concentration, respectively).

Several lab tests are useful in the management of chronic DM. Home glucose testing can show trends of hyper- and hypoglycemia. The HbA1c test indicates the extent of glycation due to hyperglycemia over three months (the life of the red blood cell). Urine albumin testing can identify the early stages of diabetic nephropathy. Since patients with diabetes are also prone to cardiovascular disease, serum lipid monitoring is advisable at the time of diagnosis. Similarly, some recommend monitoring thyroid status by obtaining a blood level of thyroid-stimulating hormone annually due to a higher incidence of hypothyroidism.

Treatment / Management:

The physiology and treatment of diabetes are complex and require a multitude of interventions for successful disease management. Diabetic education and patient engagement are critical in management. Patients have better outcomes if they can manage their diet (carbohydrate and overall caloric restriction), exercise regularly (more than 150 minutes weekly), and independently monitor glucose. Lifelong treatment is often necessary to prevent unwanted complications. Ideally, glucose levels should be maintained at 90 to 130 mg/dL and HbA1c at less than 7%. While glucose control is critical, excessively aggressive management may lead to hypoglycemia, which can have adverse or fatal outcomes.

Since T1DM is a disease primarily due to the absence of insulin, insulin administration through daily injections, or an insulin pump, is the mainstay of treatment. In T2DM, diet and exercise may be adequate treatments, especially initially. Other therapies may target insulin sensitivity or increase insulin secretion by the pancreas. The specific subclasses for drugs include biguanides (metformin), sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, glucagonlike-peptide-1 agonist, dipeptidyl peptidase IV inhibitors (DPP-4), selective, amylinomimetics, and sodium-glucose transporter-2 (SGLT-2) inhibitors. Metformin is the first line of the prescribed diabetic medications and works by lowering basal and postprandial plasma glucose. Insulin administration may also be necessary for T2DM patients, especially those with inadequate glucose management in the advanced stages of the disease. In morbidly obese patients, bariatric surgery is a possible means to normalize glucose levels. It is recommended for individuals who have been unresponsive to other treatments and who have significant comorbidities.[29] The GLP-1 agonists liraglutide and semaglutide correlate with improved cardiovascular outcomes. The SGLT-2 inhibitors empagliflozin and canagliflozin have also shown to improve cardiovascular outcomes along with potential renoprotection as well as prevention for the development of heart failure.

Regular screenings are necessary since microvascular complications are a feared complication of diabetes. Regular diabetic retinal exams should be performed by qualified medical personnel to assess for diabetic retinopathy. Neurologic examination with monofilament testing can identify patients with neuropathy at risk for amputation. Clinicians can also recommend patients perform daily foot inspections to identify foot lesions that may go unnoticed due to neuropathy. Low-dose tricyclic antidepressants, duloxetine, anticonvulsants, topical capsaicin, and pain medications may be necessary to manage neuropathic pain in diabetes. Urine microalbumin testing can also assess for early renal changes from diabetes with albuminuria greater than 30mg/g creatinine along with the estimated GFR. The antiproteinuric effect of the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin receptor blockers (ARBs) makes them the preferred agents to delay the progression from microalbuminuria to macroalbuminuria in patients with both Type 1 or Type 2 diabetes mellitus.

The FDA has approved pregabalin and duloxetine for the treatment of diabetic peripheral neuropathy. Tricyclic antidepressants and anticonvulsants have also seen use in the management of the pain of diabetic neuropathy with variable success. 

The ADA also recommends regular blood pressure screening for diabetics, with the goal being 130 mmHg systolic blood pressure and 85 mmHg diastolic blood pressure. Pharmacologic therapy for hypertensive diabetics typically involves angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, diuretics, beta-blockers, and/or calcium channel blockers. The ADA recommends lipid monitoring for diabetics with a goal of low-density lipoprotein cholesterol (LDL-C) being less than 100 mg/dL if no cardiovascular disease (CVD) and less than 70 mg/dl if atherosclerotic cardiovascular disease (ASCVD) is present. Statins are the first-line treatment for the management of dyslipidemia in diabetics. The ADA suggests that low dose aspirin may also be beneficial for diabetic patients who are at high risk for cardiovascular events; however, the role of aspirin in reducing cardiovascular events in patients with diabetes remains unclear.

Complications:

Regardless of the specific type of diabetes, complications involve microvascular, macrovascular, and neuropathic issues. Microvascular and macrovascular complications vary according to the degree and the duration of poorly control diabetes and include nephropathy, retinopathy, neuropathy, and ASCVD events, especially if it is associated with other comorbidities like dyslipidemia and hypertension.[45] One of the most devastating consequences of DM is its effect on cardiovascular disease (ASCVD). Approximately two-thirds of those with DM will die from a myocardial infarction or stroke.[46] In T2DM, fasting glucose of more than 100 mg/dL significantly contributes to the risk of ASCVD, and cardiovascular risk can develop before frank hyperglycemia.

DM is also a common cause of blindness in adults aged 20 to 74 years in the United States. Diabetic retinopathy contributes to 12000 to 24000 new cases of blindness annually, and treatments generally consist of laser surgery and glucose control.

Renal disease is another significant cause of morbidity and mortality in DM patients. It is the leading contributor to end-stage renal disease (ESRD) in the United States, and many patients with ESRD will need to start dialysis or receive a kidney transplant.[49] If the albuminuria persists in the range of 30 to 300 mg/day (microalbuminuria), it seems to be a predictable earliest marker for the onset of diabetic neuropathy. Once macroalbuminuria (greater than 300 mg/24 hr) sets in, the progression to ESRD hastens up. The random spot urine specimen for measurement of the albumin-to-creatinine ratio is a quick, easy, predictable method that is the most widely used and preferred method to detect microalbuminuria. Two of three tests, done over a six month showing a persistent level greater than 30 mcg/mg creatinine, confirms the diagnosis of microalbuminuria.

DM is also the leading cause of limb amputations in the United States; this is primarily due to vasculopathy and neuropathy associated with DM. Many patients who develop neuropathy need to have regular foot exams to prevent infection from wounds that go unnoticed.

The duration of diabetes is the most crucial risk factor for the development of diabetic retinopathy. In people with type 1 diabetes, it typically sets in about 5 years after disease onset. Hence it is recommended to start the yearly retinal exams in these patients about five years after diagnosis. Among patients with type 2 diabetes, many patients might already have retinal changes at the time of diagnosis. Approximately 10% at ten years, 40% at 15 years, and 60% at 20 years will have nonproliferative retinal disease. In these patients, the recommendation is to start the yearly retinal screening at the time of diagnosis. Study after study has shown that reasonable glycemic control favorably affected the onset and progression of diabetic retinopathy. Uncontrolled blood pressure is an added risk factor for macular edema. Lowering the blood pressure in patients with diabetes thus also affects the risk of progression of the retinopathy. Injection of antibodies vascular endothelial growth factor (anti-VEGF) agents are generally in use as the initial therapy in cases of macular edema. In cases of nonproliferative diabetic retinopathy, pan-retinal photocoagulation is being used. In cases of diabetic proliferative retinopathy, combined modalities of anti-VEGF agents and pan-retinal photocoagulation are now in use. Sudden loss of vision can occur for several reasons in patients with diabetes mellitus, the most common being vitreous hemorrhage. Less common causes that merit consideration include vascular occlusion (central retinal vein or branch vein occlusion involving the macula), retinal detachment, end-stage glaucoma, and ischemic optic neuropathy.

Furthermore, evidence suggests that T2DM may also contribute to cancer development, specifically bladder cancer, in those using pioglitazone.[50] Patients using metformin had improved cancer-specific survival in those with prostate, pancreatic, breast, and colorectal cancers. However, it is unclear how metformin plays a role in modulating cancer in patients with diabetes.

Those with gestational diabetes are at a higher risk for cesarean delivery and chronic hypertension. Pregnant patients with T2DM generally have a better prognosis in terms of neonatal and pregnancy complications compared to those with T1DM. Generally, neonates of DM mothers will present with hypoglycemia and macrosomia.

The most acute complication of DM is diabetic ketoacidosis (DKA), which typically presents in T1DM. This condition is usually either due to inadequate dosing, missed doses, or ongoing infection.[53] In this condition, the lack of insulin means that tissues are unable to obtain glucose from the bloodstream. Compensation for this causes the metabolism of lipids into ketones as a substitute energy source, which causes systemic acidosis, and can be calculated as a high anion-gap metabolic acidosis. The combination of hyperglycemia and ketosis causes diuresis, acidemia, and vomiting leading to dehydration and electrolyte abnormalities, which can be life-threatening. In T2DM, hyperosmolar hyperglycemic syndrome (HHS) is an emergent concern. It presents similarly to DKA with excessive thirst, elevated blood glucose, dry mouth, polyuria, tachypnea, and tachycardia. However, unlike DKA, HHS typically does not present with excessive urinary ketones since insulin still gets produced by pancreatic beta cells. Treatment for DKA or HHS involves insulin administration and aggressive intravenous hydration. Careful management of electrolytes, particularly potassium, is critical in the management of these emergent conditions.