Sandbox:Vellayat

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vellayat Ali M.B.B.S[2]

GOUT

DIAGNOSIS 

The favored approach to the diagnosis of gout is based upon the identification of intracellular monosodium urate (MSU) crystals found in the synovial fluid aspirate of an affected joint, under polarizing light microscopy. But when this is not possible, a clinical diagnosis can be deduced with the help of clinical features, the history and physical examination, laboratory findings, and various imaging studies. 18299687 

Diagnosis of acute gout

In the event of acute gout attack, diagnosis must be confirmed by arthrocentesis of the acutely inflamed joint, even when the clinical scenario strongly points to a gouty flare,.; Lally EV, Zimmerman B, Ho G Jr, Kaplan SR. Uratemediated inflammation in nodal arthritis: clinical and roentgenographic correlations. Arthritis Rheum. 1989;32:86-90 

Synovial fluid should be examined readily under routine light and polarizing light microscopy and looked for negatively birefringent needle-shaped MSU crystals. McCarty DJ, Hollander JL. Identification of urate crystals in gouty synovial fluid. Ann Intern Med. 1961;54:452-460 

In addition, testing of the synovial fluid for cell counts with differential, gram staining and culture should also be done. 

The sensitivity of this technique in demonstrating negatively birefringent intra- and extracellular crystals in patients with gout flares is at least 85 percent, and the specificity for gout is 100 percent. 856219 16462524. The sensitivity of can be improved by examination of the sediment in a centrifuged specimen. 10803751 

Clinical diagnostic criteria-based diagnosis of a gout flare — In patients with a gout flare in whom crystal diagnosis is not achieved, confirmation of the diagnosis of gout can be made in the gout flare setting in the absence of synovial fluid or when the polarized light microscopic study of aspirated synovial fluid is negative by use of a "diagnostic rule" utilizing a set of validated clinical, historic, and laboratory criteria [77,78. An alternative and potentially complementary approach in such patients is use of imaging techniques to demonstrate crystal deposition noninvasively; this approach also requires particular expertise in the relevant imaging techniques and their interpretation.

Use of a clinical diagnostic rule — A clinical diagnostic approach ("rule"), which can be used to estimate the likelihood of gout, has been shown to improve the accuracy of diagnosis of a gout flare made in primary care practice without joint fluid analysis [77]. The model uses seven variables (which were assigned weighted scores) that can be ascertained in primary care to distinguish three levels of risk for gout. It uses the following variables and scoring values:

●Male sex (2 points)

●Previous patient-reported arthritis flare (2 points)

●Onset within one day (0.5 points)

●Joint redness (1 point)

●First metatarsal phalangeal joint involvement (2.5 points)

●Hypertension or at least one cardiovascular disease (1.5 points)

●Serum urate level greater than 5.88 mg/dL (3.5 points)

Based upon the total score, patients can be identified as having low (≤4 points), intermediate (>4 to <8 points), or high (≥8 points) probability of gout. In addition, the authors of the rule have developed a calculator for clinical use that provides a more precise absolute calculated risk of gout for the individual pat

In patients with an intermediate score, a tentative diagnosis of gout for the purpose of clinical management may still be made in the absence of crystals based upon a preponderance of evidence otherwise favoring the diagnosis (eg, inflammatory joint fluid in a patient with evidence of or known gout in the absence of infection, especially with a score in the higher part of the intermediate range). An alternative diagnosis should be sought in patients lacking sufficient features to support a tentative diagnosis of gout.

The diagnostic rule was validated by application to another cohort of 390 patients with monoarthritis who could conceivably have had gout and were referred to rheumatologists in a regional gout research center in the Netherlands by primary care and other specialty clinicians [78].

Role of imaging in diagnosis — We employ ultrasonography of affected joints selectively in patients with histories of multiple episodes of acute intermittent inflammation, especially when those episodes have involved one or a few specific joints, aspiration of synovial fluid is not feasible, urate crystals have not been detected by prior polarized light microscopic examination, and the diagnosis of gout remains uncertain.

Even though the sensitivity and specificity of ultrasonography and dual-energy computed tomography (DECT) in the diagnosis of early gout was best established in more advanced disease, crystal deposition can be demonstrated by this approach in affected patients by practitioners with appropriate expertise. (See 'Imaging' above.)

The ready availability of ultrasonography in the clinic, the identification of abnormalities with high specificity for gout by this method, and its additional capacity to serve as the basis for directed needle aspiration of joint fluid for polarized light microscopy support this approach, which may be undertaken either in the course of an acute inflammatory episode or during an intercritical period. (See 'Imaging' above and 'Diagnosis of intercritical or tophaceous gout' below.)

We limit the use of DECT examination for gout diagnosis to patients in whom, despite more chronic arthropathy or deformity, a urate crystal deposition basis for the causative disorder has not been confirmed by polarized light microscopic examination of joint aspirates, pathologic analysis of tissue samples (see 'Histologic examination' below), or alternative imaging modalities, including magnetic resonance imaging (MRI). (See 'Imaging' above.)

Diagnosis of intercritical or tophaceous gout

Crystal demonstration in aspirates of synovial fluid or tophi — Even during the asymptomatic intercritical period, urate crystals are identifiable in synovial fluid from previously affected joints in virtually all untreated gouty patients and in approximately 70 percent of those receiving urate-lowering therapy [80-82]. This allows late establishment of the diagnosis in the majority of patients in whom the diagnosis was not made in the acute setting.

The high prevalence of urate crystals in aspirates from joints previously affected only once supports the view that deposition of urate crystals in and about joints precedes the first clinical episode of gout by a substantial period of time in most instances.

Demonstration of urate crystals in aspirates of tophaceous deposits provides a convenient and specific means to corroborate the diagnosis in gouty individuals with tophi [83].

Histologic examination — Ideally, tissues that are being prepared for histologic examination for urate crystals should be examined as fresh or frozen sections or should be preserved in alcohol (rather than in formalin) and later stained with a nonaqueous system such as Wright-Giemsa stain. However, formalin-fixed, paraffin-embedded tissue has been reported to still occasionally have demonstrable birefringent urate crystals if stained with a nonaqueous technique using alcoholic eosin [84]. Aqueous stains, such as hematoxylin and eosin, allow urate crystals to dissolve, leaving behind a nondiagnostic eosinophilic matrix that may have foreign body giant cells.

Clinical diagnosis of intercritical gout — In the absence of the means to identify urate crystals or in the presence of a negative polarized light microscopic study, a provisional diagnosis of gout is made by a combination of clinical and historic criteria. However, non-crystal diagnostic criteria for a gout flare have been validated only for the gout flare setting, and their application to diagnosis of patients in intercritical period awaits validation. (See 'Use of a clinical diagnostic rule' above.)

Imaging of a previously inflamed "gouty joint" that has become persistently symptomatic may also be productive either in identifying typical features of gout (and/or intercurrent infection) or in guiding needle aspiration of the affected joint for corroboration of crystal diagnosis, intercurrent infection, or both in the joint or adjacent bone. (See 'Imaging' above and 'Role of imaging in diagnosis' above.)

Classification criteria for gout — Classification criteria for the purpose of identifying a homogeneous group of patients with gout for clinical, genetic, and epidemiologic study (but not for clinical diagnosis) have been developed by an international collaborative effort of the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) and are based upon studies of patients representing a broad array of ethnicities and geographic sites [85,86].

These 2015 criteria permit classification as having gout in patients with at least one episode of swelling, pain, or tenderness in a peripheral joint or bursa with either the presence of MSU crystals in a symptomatic joint, bursa, or tophus or without positive synovial fluid findings (whether or not arthrocentesis has been attempted) in individuals with a sufficient number and type of a series of well-defined clinical and imaging findings. However, a negative search for MSU crystals reduces the calculated score.

Among patients with at least one episode of swelling, pain, or tenderness in a peripheral joint or bursa, the classification criteria have a sensitivity and specificity of 92 and 89 percent, respectively [85,86]. This classification scheme, while of direct benefit to researchers, has not been evaluated for its utility in clinical practice, where joint, bursa, or tophus aspiration remains central to establishing a diagnosis of gout in the view of the investigators who developed the criteria set.

It is important to distinguish between diagnostic [77,78,87] and classification [74,75,88,89] criteria when considering the development of robust and accurate schemes for diagnosing, treating, and studying any disease [90]. Diagnostic criteria are a set of signs, symptoms, and tests developed for use in routine clinical care of individual patients and thus have treatment implications. By contrast, classification criteria are standardized definitions primarily aimed at enabling clinical studies to have uniform cohorts for research and have no direct treatment implications for patients.

Classification criteria for diseases are possible to develop whether or not there is a "gold standard" diagnostic criterion, but diagnostic criteria, which require levels of specificity and sensitivity approaching 100 percent, are more problematic to achieve, except for diseases with a true gold standard, like urate crystals in gout. When a gold standard for diagnosis exists, diagnostic and classification criteria for that disease can be very similar, but the underlying aims of the processes involved will necessarily perpetuate differences in the appropriateness of applying individual criteria, even if validated for one purpose, to the other category (eg, using classification criteria for clinical diagnostic purposes).

DIAGNOSTIC STUDY OF CHOICE

  

Synovial Fluid Analysis: 

Synovial fluid is aspirated off the inflamed joint by careful arthrocentesis. 

Joint fluid is then analyzed for the presence of characteristic negatively birefringent monosodium urate crystals appearing needle-like structures under polarized microscopy. This is central to confirm the diagnosis of gout. 22303530 18299687 

The sensitivity of this technique in demonstrating negatively birefringent crystals in patients with gout flares is at least 85 percent, and the specificity for gout is 100 percent. 856219 16462524   

HISTORY & PHYSICAL EXAMINATION 

In his classic description of a gouty attack, translated from Latin in 1848, Sir Thomas Sydenham wrote;

the victim goes to bed and sleeps in good health. About two o'clock in the morning he is awakened by a severe pain in the great toe; more rarely in the heel, ankle, or instep. This pain is like that of a dislocation...Then it is a violent stretching and tearing of the ligaments--now it is a gnawing pain and now a pressure and tightening...He cannot bear the weight of bedclothes nor the jar of a person walking in the room. The night is passed in torture, sleeplessness, turning of the part affected, and perpetual change of posture; the tossing about of the body being as incessant as the pain of the tortured joint.

Medical Therapy

The goal of medical therapy in gout is to: 

·      Provide effective treatment in acute gout attack

·      Prevent acute flares through prophylaxis

·      lower uric acid levels to prevent flares of gouty arthritis and to prevent deposition of urate crystals in body tissue 

In 2012, the American College of Rheumatology (ACR) published guidelines for management of gout. It includes systemic nonpharmacological and pharmacological therapeutic approaches to hyperuricemia as well as therapy and anti-inflammatory prophylaxis on acute gouty arthritis. A brief descript of the recommendations is as follows:  

Treatment for acute gouty arthritis 

·      Acute gout attack should be treated with pharmacologic therapy (evidence C), and that treatment should be preferentially initiated within first 24 hours of onset (evidence C).

·      Access the intensity of the attack based on severity of pain and the number of joints involved.

·      For a mild/moderate gout severity (6 of 10 on a 0 –10 pain visual analog scale) involving 1 or a few small joints or 1 or 2 large joints, initiating monotherapy with options being oral nonsteroidal anti-inflammatory drugs (NSAIDs), systemic corticosteroids, or oral colchicine (evidence A for all drug categories).

o  NSAIDs: Approved medications are naproxen, indomethacin (both evidence A), and sulindac (evidence B). They should be initiated at their full dosing at either the Food and Drug Administration (FDA)– or European Medical Agency–approved anti-inflammatory/ analgesic doses. It should not be tapered with symptomatic improvement; instead full dose should be administered till complete resolution.

o  Colchicine: Acute gout can be treated with a loading dose of 1.2 mg, followed by 0.6 mg 1 hour later (evidence B). This can then be followed by a gout attack prophylaxis dosing beginning 12 hours or later and continued till the attack resolves (evidence C). If the patient was already on prophylactic colchicine and received acute gout regimen in the last 2 weeks, then consider other therapeutic options i.e. corticosteroid, NSAID.

o  Corticosteroids: Corticosteroids can be given as an initial monotherapy. Prednisone, or prednisolone at a starting dosage of at least 0.5 mg/kg per day for 5–10 days and then discontinued (evidence A). Alternatively, a full dose for 2–5 days can be given, followed by tapering for 7–10 days, and then discontinued (evidence C). While oral corticosteroid is the preferred route, intra-articular route can be considered for acute gout of 1 or 2 large joints (evidence B).

·      For a severe acute gout attack (7 of 10 on a 0 –10 pain visual analog scale) and in patients with an acute polyarthritis or involvement of more than 1 large joint, combination therapy should be considered. Recommendation is to initiate simultaneous use of full doses (or, where appropriate, a full dose of 1 agent and prophylaxis dosing of the other) of 2 of the pharmacologic modalities as recommended above.

·      If the patient was previously on an established pharmacologic uric acid lowering therapy (ULT), it is recommended to be continued without interruption during an acute attack (evidence C), i.e. do not stop ULT therapy during an acute flare.  

Prophylaxis to prevent acute gout flares 16339094, 21846852, 20370912, 21353107, 15570646

It is recommended that for all cases of gout, where urate lowering therapy is started, a prophylaxis for acute flares should be started as well, given that gout attacks are common in early ULT (evidence A). 16339094, 21846852, 20370912, 21353107 

The first-line for this purpose is oral colchicine (evidence A) 21353107, 15570646, or low-dose NSAIDs (evidence C). 

A low-dose of colchicine as 0.5 mg or 0.6 mg taken orally once or twice a day is the recommendation, with dosing further adjusted downward for moderate to severe renal function impairment and potential drug–drug interactions) 21480191. 

The duration of treatment should be greater of at least 6 months (evidence A) 16339094 20370912, 21353107, 3 months after achieving target serum urate levels in patient with no tophi on physical exam (evidence B), or 6 months after achieving desired urate levels appropriate for the patient with one of more tophi (evidence C). 

Management of chronic gout/chronic tophaceous gouty arthropathy:

 

Once the diagnosis of gout is established, a systematic pharmacologic as well as non-pharmacologic management approach should be initiated. A set of baseline recommendations for all patients are: 

·      Patient education on the disease, its treatment options and their objectives, including the particular role of uric acid excess in gout and as the key long-term treatment target (evidence B) 22679303.

·      Consider diet and lifestyle modification

·      Always consider elimination of serum urate– elevating prescription medications e.g. thiazide and loop diuretics, niacin, and calcineurin inhibitors (evidence C)

·      Always consider secondary causes of hyperuricemia for all gout patients

·      A clinical evaluation of gout disease activity and its burden should be done for each patient by history and a thorough physical examination for symptoms of arthritis and signs such as tophi and acute and chronic synovitis (evidence C).  

Nonpharmacological urate lowering therapy

 

Certain diet and lifestyle measures are advised for the majority of patients with gout (evidence B and C for individual measures). Many of them are recommended for decreasing the risk and frequency of acute gout attacks (20035225) and also to lower serum urate levels.

This emphasis on diet and lifestyle choices is to promote and maintain ideal health as well as for the prevention and optimal management of comorbidities in gout patients, which include cardiovascular diseases 16871533, 18504339, diabetes mellitus, hyperlipidemia, and hypertension. 

Gout patients should limit their consumption of purine-rich meat and seafood (evidence B) (22648933) as well as high fructose corn syrup–sweetened soft drinks and energy drinks (evidence C), and encouraged the consumption of low-fat or nonfat dairy products (evidence B) (21285714).

Alcohol intake is advised to be reduced for all gout patients, especially of beer (evidence B). In CTGA and in patients with inadequate control of disease, abstinence is recommended during periods of active arthritis (evidence C). 

Pharmacological urate lowering therapy (ULT) and serum urate target

Pharmacological therapy to lower serum uric acid levels is indicated in any patient with established diagnosis of gout with

·      Prior gout attacks (2 or more per year) and current hyperuricemia (evidence A )

·      Tophus or tophi by clinical exam or imaging study (evidence A)

·      CKD stage 2–5 or end-stage renal disease, which by itself, is an appropriate indication for pharmacologic ULT (evidence C)

·      Past urolithiasis (evidence C) 

The goal is to attain a serum urate level at a minimum of less than 6 mg/dl (evidence A). Serum urate level should be lowered sufficiently so to have a dependable improve in signs and symptoms of the disease, including palpable and visible tophi detected by physical examination, and that this may involve therapeutic serum urate level lowering to below 5 mg/dl (evidence B). 

The recommended first line is xanthine oxidase inhibitor therapy with either allopurinol or febuxostat (evidence A). There is no preference of either XOI over the other XOI drug. ULT can be started during an acute gout attack, provided an effective anti-inflammatory therapy has already been initiated (evidence C)

·      Allopurinol should be started with a dose no greater than 100 mg/day (50 mg/day in stage 4 or worse CKD) (evidence B), then gradually titrate maintenance dose upward every 2–5 weeks to appropriate maximum dose in order to achieve desired serum uric acid level (evidence C) Prior to initiation, in selected patient subpopulations at higher risk for severe allopurinol hypersensitivity reaction (e.g., Koreans with stage 3 or worse CKD, and Han Chinese and Thai irrespective of renal function), consider HLA–B*5801 (evidence A)

·      Probenecid is the first choice among uricosuric agents (evidence B). It is recommended to monitor urinary uric acid levels during its therapy (evidence C). With a creatinine clearance of 50 ml/minute, it is not recommended as first-line ULT monotherapy (evidence C). History of urolithiasis and elevated uric acid level in urine also contraindicates its use (evidence C). Monitor urinary pH and consider urine alkalinization (e.g., with potassium citrate), in addition to increased fluid intake, as a risk management strategy for urolithiasis (evidence C).  

Probenecid was recommended as an alternative first-line option in case of contraindication or intolerance to at least 1 xanthine oxidase inhibitor (evidence B). However, probenecid should not be used as a first-line monotherapy when creatinine clearance is below 50 ml/minute. 

It is recommended that regular monitoring of serum urate levels be done every 2–5 weeks during drug titration; including continued measurements every 6 months once the desired level is achieved (evidence C). 

 

 

Sydenham T. The Works of Thomas Sydenham, MD. Translated by RG Latham. Vol II. London: Sydenham Society; 1848:124.

Interstitial lung disease

Lung Response: Granulomatous

Lung Response: Alveolitis, Interstitial Inflammation, and Fibrosis

Known

Idiopathic (Unknown)

Hypersensitivity pneumonitis (organic dusts)

Inorganic dusts

Sarcoidosis

Lymphomatoid granulomatosis

Granulomatous vasculitides

Bronchocentric granulomatosis

Beryllium

Silica

Eosinophilic granulomatosis with polyangiitis (Churg Strauss syndrome)

Granulomatosis with polyangiitis (Wegener's)

Known cause

Idiopathic (Unknown)

Drug-induced pulmonary toxicity

Occupational and environmental exposure

Radiation-induced lung injury

Aspiration pneumonia

Smoking-related

Residual of acute respiratory distress syndrome

Inhaled inorganic dust

Inhaled organic dusts

Inhaled agents other than inorganic or organic dusts

Desquamative interstitial pneumonia

Respiratory bronchiolitis–associated interstitial lung disease

Pulmonary Langerhans cell granulomatosis

Pulmonary alveolar proteinosis

Idiopathic interstitial pneumonias

Lymphocytic infiltrative disorders (lymphocytic interstitial pneumonitis associated with connective tissue disease)

Connective tissue diseases

Gastrointestinal or liver diseases

Inherited diseases

Graft-versus-host disease

Pulmonary hemorrhage syndromes

Eosinophilic pneumonias

Lymphangioleiomyomatosis

Amyloidosis

Major idiopathic interstitial pneumonias

Rare idiopathic interstitial pneumonias

Unclassifiable idiopathic interstitial pneumonias

• Idiopathic pulmonary fibrosis • Idiopathic nonspecific interstitial pneumonia • Respiratory bronchiolitis-interstitial lung disease • Desquamative interstitial pneumonia • Cryptogenic organising pneumonia • Acute interstitial pneumonia

• Idiopathic lymphoid interstitial pneumonia • Idiopathic pleuroparenchymal fibroelastosis

• Systemic lupus erythematosus • Rheumatoid arthritis • Ankylosing spondylitis • Systemic sclerosis • Sjögren syndrome • Polymyositis • Dermatomyositis

• Crohn disease • Primary biliary cirrhosis • Chronic active hepatitis • Ulcerative colitis

• Tuberous sclerosis • Neurofibromatosis • Niemann-Pick disease • Gaucher disease • Hermansky-Pudlak syndrome

• Bone marrow transplantation • Solid organ transplantation

• Goodpasture syndrome • Idiopathic pulmonary hemosiderosis • Isolated pulmonary capillaritis

Type of respiratory failure	Causes/Etiology		Onset	Clinical manifestations					Investigations		Gold standard	Other features
				Symptoms				Physical exam
				Dyspnea	Cough	Fever	Others findings		Imaging	Labs
Hypoxic respiratory failure (Type 1 respiratory failure)	Cardiogenic pulmonary edema	Acute decompensated heart failure	Acute	+	+ with frothy expectoration	+/-	nausea and anorexia confusion headaches	Wheezing Increased pulse rate Crackles Pedal edema Elevated JVP Obtundation Enlarged liver	Cardiomegaly and interstitial edema in chest radiograph Echocardiography	Pulse oximetry Assays for BNP (B-type natriuretic peptide) and NT-proBNP (N-terminal pro-B-type natriuretic peptide) Cardiac troponin levels ST and T waves abnormalities in ECG	Clinical diagnosis	History of heart disease, hypertension
	Non cardiogenic pulmonary edema	Adult respiratory distress syndrome (ARDS)	Acute	+	+/-	+/-	Cyanosis	Tachypnea Tachycardia Diffuse crackles	Diffuse, bilateral, alveolar infiltrates without cardiomegaly in chest radiograph Bilateral opacities in CT	Hypoxemia with acute respiratory alkalosis in arterial blood gases	Clinical diagnosis with supportive test	According to Berlin definition: One week of new or worse respiratory symptoms or clinical insult Symptoms can not be explained by cardiac disease Bilateral opacities in chest X-Ray or CT Compromised oxygenation
		High-Altitude Pulmonary edema (HAPE)	Acute	+	+ with frothy expectoration	+	Chest tightness Decreased exercise performance	Wheezing	Chest X-ray may show patchy alveolar infiltrates, predominantly in the right central hemithorax, which become more confluent and bilateral as the illness progresses	High levels of white blood cell count Decreased of oxygen saturation	Clinical diagnosis with supportive test	Occurrs over 2500 m Descent is mandatory in >4000 m
		Neurogenic pulmonary edema	Acute	+	+/- with frothy expectoration	+/-	Hemoptysis	Rales Bilateral crackles	Bilateral hyperdense infiltration in chest X-Ray	CBC may show Leukocytosis Bilateral hyperdense infiltrations on chest X-Ray	Diagnosis of exclusion A proposed criteria is as follows Bilateral infiltrates PaO2/FiO2 ratio < 200 No evidence of left atrial hypertension Presence of CNS injury Absence of other common causes of acute respiratory distress or ARDS	Major causes of NPE are epileptic seizures, cerebral hemorrhages and brain injury
		Pulmonary embolism	Acute Sub-acute Chronic	+	+	+/-	Chest pain Orthopnea	Wheezing Tachypnea Edema Decreased breath sounds Tachycardia	Hamptom and Westermark sign may be seen in chest X-Ray	Leukocytosis, elevated erythrocyte sedimentation and lactic acid in complete blood count Hypoxemia in arterial blood gas D-dimer to rule out other diseases Tachycardia and abnormalities in ST-segment and T waves are observed in ECG VQ scan	Computed tomography pulmonary angiogram (CTPA) or catheter based pulmonary angiography	Venous thromboembolism (VTE)
	Pneumonia		Acute	+	+ with sputum production	+	Pleuritic chest pain	Egophony Crackles Tactile fremitus Bronchial breath sounds	Infiltration in chest X-Ray	Leukocytosis Sputum culture & sensitivity	Clinical manifestations and infiltration chest X-Ray with or without microbiological test	Community-acquired pneumonia Hospital-acquired pneumonia Healthcare-associated pneumonia Ventilator-associated pneumonia Aspiration pneumonia
	Idiopatic chronic lung fibrosis		Chronic	+	+ without any sputum production	+/-	symptoms suggestive of rheumatic diseases may be present	Clubbing of the digits Bibasilar Crackles	Reticular or nodular pattern in chest X-Ray HRCT may show reticular opacities, including honeycomb changes and traction bronchiectasis	Serological tests e.g. ANA, RF for underlying rheumatological diseases Reduced FEV1 and FVC on spirometry	Clinical presentation in combinations with HRCT findings Lung biopsy when lab, imaging and PFT do not yield enough evidence	History of cigarette smoking
Hypercapnic respiratory failure (Type 2 respiratory failure)	COPD		Acute Chronic Acute-on-chronic	+	+	+/-	Exercise intolerance Acute exacerbation may affect CNS, ranging from irritability to decreased responsiveness	Clubbing Tachypnea Barrel shaped chest Decreased breath sounds with prolonged expiration Rhonchi and Wheeze Use of accessory respiratory muscles Increased JVP, peripheral edema may manifest with right ventricular overload during an acute exacerbation	Chest X-ray may show hyperinflation, flattened diaphragm, rapid tapering of vascular markings  CT scan helps to correlate with COPD prognosis	PFTs: (FEV1/FVC) <70% of predicted    ABGs: Mild to moderate hypoxemia, hypercapnia with progression of disease, pH is around normal, < 7.3 points to respiratory acidosis	Clinical diagnosis with supportive test	CNS symptoms may be the only manifestation in elderly with baseline hypercapnia
	Severe Asthma/Status Asthmaticus		Acute	+	+	-	Chest tightness Audible wheeze	Tachypnea Tachycardia Wheezing Use of accessory respiratory muscles Unable to speak full sentences Orthopnea Pulsus paradoxus	Chest X-ray not required in acute conditions, may show hyperinflation	PEF <40 percent predicted or personal best Pulse oximetry ABGs	Clinical diagnosis	History of bronchial asthma
	Drug Overdose (opioid toxicity)		Acute	+	-	-	Nausea and vomiting Constipation Seizures	Classic triad suggesting opioid toxicity consist of respiratory depression, pinpoint pupils, and altered mental state  Conjunctival injection, Decreased bowel sounds Euphoria	Chest X-ray usually not required, may show signs of acute lung injury	Urine toxicology screen: may reveal polysubstance abuse	Clinical diagnosis with supportive test	Toxicity from antipsychotics, anticonvulsants, ethanol, and sedatives can result in miosis and altered mentation, but respiratory depression is usually absent
	Myasthenic crisis		Acute	+	+/-	+/-	Inability to cough Bulbar weakness: dysphagia, nasal regurgitation, a nasal quality to speech, staccato speech, jaw weakness, bi-facial paresis, and tongue weakness	Expressionless face with droopy eyelids and mouth Use of accessory muscles of respiration i.e. external intercostal muscles, sternocleidomastoid, scalene muscles Rapid and shallow breathing	Chest X-ray findings depicting bacterial pneumonia and/or aspiration may be observed	Pulse Oximetry ABGs CBC: Infective cause precipitating the crisis may be observed Tensilon (edorphonium) test	Clinical diagnosis with supportive test	Known case of Myasthenia Gravis In some cases, respiratory failure may be the presenting symptom
	Guillain-Barré syndrome		Acute	+	-	+/-	Difficulty walking (ascending symmetric muscular weakness) Paresthesias in hands and feet Back pain Pain in extremities	Dysautonomia (tachycardia/bradycardia, hypertension/hypotension, urinary retention) Diminished or absent deep tendon reflexes Limb weakness (first lower then upper limbs) Facial droop (Facial nerve palsy) Ophthalmoparesis (3rd & 6th nerve palsies) Decreased breath sounds Decreased bowel sounds	MRI Spine: thickening of intrathecal spinal nerve roots and cauda equina	CSF analysis: Albuminocytologic dissociation Nerve conduction studies may show conduction block, slowed motor conduction velocities and delayed latencies PFTs: Vital Capacity, maximum inspiratory pressure (PImax) and maximum expiratory pressure (PEmax) should be followed to determine appropriate timing of intubation and mechanical ventilation	Clinical diagnosis with supportive test	Signs depicting respiratory failure occur late, early manifestations are tachypnea, tachycardia, air hunger, broken sentences, and a need to pause between sentences Use of the accessory respiratory muscles, paradoxical breathing, and orthopnea indicate severe diaphragmatic weakness
Perioperative respiratory failure (Type 3 respiratory failure)	Post-operative atelectasis		Acute	+	+/-	+/-	Asyptomatic or increase work of breathing	Tachypnea Tachycardia Decreased movement in the affected lung area Dullness percussion note Absent breath sounds Tracheal deviation to affected side	Chest X-ray may show increased density and reduced volume CT chest accurately shows the involved segment	Pulse oximetry ABGs	Clinical diagnosis with support of radiographic findings	History of abdominal or thoracic surgery
Type 4 respiratory failure	Shock		Acute	+	-	+/-	Oliguria Abnormal mental status Clammy skin Cool extremities	Hypotension Tachycardia Tachypnea Rales Gallop rythm	Visible congestion in chest X-Ray	Electrocardigogram Increased levels of lactic acid Low levels of Bicarbonate Echocardiography to identify any cardiac dysfunction	Clinical diagnosis with supportive test	Cardiac index decreased Troponin leves, chemestry screen, complete blood count Cardiogenic shock Septic shock Hypovolemic shock

Overview

underlying condition	Onset of respiratory failure	Physical examination	Symptoms	Labs and imaging	others
COPD	Acute Chronic Acute on chronic	Clubbing Tachypnea Barrel shaped chest Decreased breath sounds with prolonged expiration Rhonchi and Wheeze Use of accessory respiratory muscles Increased JVP, peripheral edema may manifest with right ventricular overload during an acute exacerbation.1	Dyspnea Cough with/without sputum Exercise intolerance Acute exacerbations may affect CNS, ranging from irritability to decreased responsiveness. CNS symptoms may be the only manifestation in elderly with baseline hypercapnia.2	Chest X-ray: hyperinflation, flattened diaphragm, rapid tapering of vascular markings  PFTs: (FEV1/FVC) <70% of predicted    ABGs: Mild to moderate hypoxemia, hypercapnia with progression of disease, pH is around normal, below 7.3 points to respiratory acidosis	History of smoking, cough and sputum production
Severe Asthma/Status Asthmaticus	Acute	Tachypnea Tachycardia Use of accessory respiratory muscles Unable to speak full sentences Orthopnea Pulsus paradoxus	Dyspnea Wheezing Cough Chest tightness	PEF <40 percent predicted or personal best Pulse oximetry Chest X-ray: not required in acute conditions, may show hyperinflation	Hx of Bronchial asthma Presence of Drowsiness3 and silent chest is a useful predictor of impending respiratory failure

We, therefore, propose the following diagnostic criteria for this subset of NPE: 1)

Acute hypercapnic respiratory failure: the patient will have no, or minor, evidence of preexisting respiratory disease, and arterial blood gas tensions will show a high Paco₂, low pH, and normal bicarbonate.

▪

Chronic hypercapnic respiratory failure: evidence of chronic respiratory disease, high Paco₂, near normal pH, high bicarbonate.

▪

Acute-on-chronic hypercapnic respiratory failure: an acute deterioration in an individual with significant preexisting hypercapnic respiratory failure, high Paco₂, low pH, high bicarbonate.

Glycogen Storage Disease Type IV

Synonyms: GSD IV, Andersen Disease, Brancher deficiency; Amylopectinosis; Glycogen Branching Enzyme Deficiency, Glycogenosis IV

 

Overview:

 

Historical Perspective:  

- In 1952, B Illingworth and GT Cori observed accumulation of an abnormal glycogen (resembling amylopectin) in the liver of a patient with von Gierke’s Disease. They postulated this finding to a different type of enzymatic deficiency, and thus to a different type of glycogen storage disease.[1]

- In 1956, DH Andersen, an American pathologist and pediatrician, reported the first clinical case of the disease as "familial cirrhosis of the liver with storage of abnormal glycogen".[2]

- In 1966, BI Brown and DH Brown clearly demonstrated the deficiency of glycogen branching enzyme (alpha-1,4-glucan: alpha-1,4-glucan 6-glycosyl transferase) in a case of Type IV glycogenosis.[3]

 

Classification

There is no established system for the classification of GSD Type IV. The deficiency of GBE affecting the liver, the brain, the heart, and skeletal muscles leads to variable clinical presentations. Based on organ/tissue involvement, age of onset and clinical features, Andersen disease can be segregated into various forms [16] as below:

Form of Presentation	Age of  Onset	Clinical Features
Classic Hepatic Form     Neuromuscular form      A-Perinatal             B-Congenital         C-Late childhood form        D-Adult form	0-18 Mo         In utero      At birth          0-18 yrs    >18-21 yrs (any age in adulthood)	Infants present with failure to thrive, and hepatosplenomegaly. Progresses to portal hypertension, ascites, and liver failure, leading to death by 5 years of age.[17]     Prenatal symptoms include, polyhydramnios, hydrops fetalis, and decreased fetal movement; at birth severe hypotonia is observed requiring mechanical ventilation for respiratory support. [18][19] Cardiac findings like progressive cardiomyopathy may also be present.[19]  Newborns may have severe hypotonia, hyporeflexia, cardiomyopathy, depressed respiration and neuronal involvement, leading to death in early infancy. [21]     Presents in childhood at any age with myopathy as exercise intolerance, and cardiopathy as exertional dyspnea; and congestive heart failure in progressed cases. [21].   May present as isolated myopathy [23] or as Adult Polyglucosan Body Disease (APBD) [22]

Adult polyglucosan body disesase (APBD)

 

- Adult polyglucosan body disease is one of the neuromuscular variant of GSD Type IV.

- Typically, the first clinical manifestation is of urinary incontinence (secondary to neurogenic bladder), followed by gait disturbance (due to spastic paraplegia) and lower limb paresthesias (due to axonal neuropathy). [15]

Pathophysiology:

Pathogenesis:

-       Glycogen storage disease type IV is an autosomal recessive genetic disorder which results due to deficiency of glycogen branching enzyme (GBE).[4]

-       During Glycogenesis, the branching enzyme introduces branches to growing glycogen chains by transferring α-1,4-linked glucose monomers from the outer end of a chain into an α-1,6 position of the same or neighboring glycogen chain. [6]

-       Deficiency of GBE affects the branching process, yielding a polysaccharide which has fewer branching points and longer outer chains, thus resembling amylopectin. This new amylopectin-like structure is also known as polyglucosan. [7]

-       The enzyme deficiency affects all the bodily tissues; but liver, heart, skeletal muscles, and the nervous system are mostly affected.

-       The abnormally branched glycogen accumulates as intracytoplasmic non membrane-bound inclusions in hepatocytes, myocytes, and neuromuscular system; where it increases osmotic pressure within cells, causing cellular swelling and death.[8][9]

-       The altered structure also renders glycogen to become less soluble, and this is thought to lead into a foreign body reaction causing fibrosis, and finally culminating in liver failure. [10][11]

-       In skeletal muscle, accumulation leads to muscle weakness, fatigue, exercise intolerance, and muscular atrophy. [12]

-       Regarding the heart, a wide spectrum of cardiomyopathy from dilated to hypertrophic and from asymptomatic to decompensated heart failure may occur. [13]

-       Although exact mechanism is not known, glycogen deposition in the myocardium is thought to initiate signaling pathways which cause sarcomeric hypertrophy, resulting in hypertrophic cardiomyopathy.[14] 

   

Molecular Genetics:

   •     Glycogen branching enzyme is a 702 amino acid protein encoded by GBE1 gene mapped to chromosome 3p12.2 and is transmitted as an autosomal recessive trait. [21][5] HUGO Gene Nomenclature Committee https://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:4180 The Universal Protein Resource (UniProt) http://www.uniprot.org/uniprot/Q04446

    •       Mutations in the GBE1 are responsible for enzymatic deficiency, and so far 40 pathogenic variants have been identified in individuals with GSD IV or adult-onset polyglucosan body disease (APBD).PMID: 23285490 

CAUSES: 

The cause of GSD type IV is variable deficiency of glycogen branching enzyme. The deficiency is due to various mutations of GBE1 gene encoding the single polypeptide protein. 

Differential Diagnosis:

Comparisons may be useful for a differential diagnosis as a number of other disease conditions with clinical features may present similar to those associated with GSD Type IV.

Presenting as hepatomegaly in infancy, the following glycogen metabolism disorders should be differentiated from GSD Type IV;

-GSD Type I

-GSD Type III

-GSD Type VI

-Hepatic Phosphorylase b Kinase Deficiency

Metabolic disorders presenting with muscle weakness/myopathy during infancy should also be considered;

Muscle glycogen synthase deficiency (GSD0b)

Lysosomal acid maltase deficiency (GSD II)

Glycogen debrancher deficiency (GSD III)

Muscle phosphorylase deficiency (GSD V)

Aldolase A deficiency (GSD XII)

Glycogenin-1 deficiency (GSD XV)

 

EPIDEMIOLOGY:

FREQUENCY- The frequency of all glycogen storage diseases is estimated to be 1 in 20,000 to 25,000 live births, while GSD IV is estimated to occur in 1 in 600,000 to 800,000 individuals worldwide.  NORD GHR https://ghr.nlm.nih.gov/condition/glycogen-storage-disease-type-iv#statistics

SEX- Males and females appear to be affected in relatively equal numbers [NORD] because the deficiency of glycogen-branching enzyme activity is inherited as an autosomal-recessive trait.

RACE- Familial aggregation is observed in about 30% of adult polyglucosan body disease cases especially among Ashkenazi Jewish populations. NORD

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

References

 

1.Structure of glycogens and amylopectins. III. Normal and abnormal human glycogen.

ILLINGWORTH B, CORI GT.

J Biol Chem. 1952 Dec;199(2):653-60

2. Familial cirrhosis of the liver with storage of abnormal glycogen.

ANDERSEN DH

Lab Invest. 1956 Jan-Feb; 5(1):11-20.

3. Lack of an alpha-1,4-glucan: alpha-1,4-glucan 6-glycosyl transferase in a case of type IV glycogenosis.

Brown BI, Brown DH.

Proc Natl Acad Sci U S A. 1966 Aug;56(2):725-9. 

4. Hum Mol Genet. 2011 Feb 1;20(3):455-65. doi: 10.1093/hmg/ddq492. Epub 2010 Nov 12.

Glycogen-branching enzyme deficiency leads to abnormal cardiac development: novel insights into glycogen storage disease IV. Lee YC¹, Chang CJ, Bali D, Chen YT, Yan YT.

5. Acta Myol. 2011 Oct; 30(2): 96–102.

PMCID: PMC3235878 Progress and problems in muscle glycogenoses

S. Di Mauro and R. Spiegel¹ 

6. Hum Mol Genet. 2015 Oct 15;24(20):5667-76. doi: 10.1093/hmg/ddv280. Epub 2015 Jul 21. 

7. PubMed: 15019703

Tay SK, Akman HO, Chung WK, Pike MG, Muntoni F, Hays AP, Shanske S, Valberg SJ, Mickelson JR, Tanji K, DiMauro S. Fatal infantile neuromuscular presentation of glycogen storage disease type IV. Neuromuscul Disord. 2004;14:253–60. 

8. Isolation of human glycogen branching enzyme cDNAs by screening complementation in yeast.

Thon VJ, Khalil M, Cannon JF

J Biol Chem. 1993 Apr 5; 268(10):7509-13.

9. Hum Pathol. 2012 Jun;43(6):943-51. doi: 10.1016/j.humpath.2011.10.001. Epub 2012 Feb 2. 

10. DOI: 10.1056/NEJM199101033240111

11. Severe cardiopathy enzyme deficiency in branching

Serenella Servidei, M.D., Roger E. Riepe, M.D., Claire Langston, M.D.,Lloyd Y: Tani, M.D., J. Timothy Bricker, M.D., Naoma Crisp-Lindgren, M.D.,Henry Travers, M.D., Dawna Armstrong, M.D., and

Salvatore DiMauro, M.D. 

12. National Organization for Rare Disorders (NORD): rarediseases.org/rare-diseases/andersen-disease-gsd-iv/

13. http://dx.doi.org/10.1155/2012/764286

14. DOI: 10.1056/NEJMra0902923 

15. Ann Neurol. 2012 Sep;72(3):433-41. doi: 10.1002/ana.23598. Adult polyglucosan body disease: Natural History and Key Magnetic Resonance Imaging Findings.

Mochel F¹, Schiffmann R, Steenweg ME, Akman HO, Wallace M, Sedel F, Laforêt P, Levy R, Powers JM, Demeret S, Maisonobe T, Froissart R, Da Nobrega BB, Fogel BL, Natowicz MR, Lubetzki C, Durr A, Brice A, Rosenmann H, Barash V, Kakhlon O, Gomori JM, van der Knaap MS, Lossos A. 

16. American Journal of Medical Genetics 139A:118–122 (2005)  

17. Bao, Y., Kishnani, P., Wu, J.-Y., Chen, Y.-T. Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. J. Clin. Invest. 97: 941-948, 1996. 

18. Neonatal presentation of lethal neuromuscular glycogen storage disease type IV L F Escobar, S Wagner, M Tucker & J Wareham Journal of Perinatology 32, 810–813 (2012) doi:10.1038/jp.2011.178 

19. Neonatal type IV glycogen storage disease associated with “null” mutations in glycogen branching enzyme 1 Andreas R.Janecke MD Susanne Dertinger MD Uwe-Peter Ketelsen MD Lothar Bereuter MD Burkhard Simma MD Thomas Müller MD Wolfgang Vogel MD Felix A. Offner MD

https://doi.org/10.1016/j.jpeds.2004.07.024  

20. Magoulas PL, El-Hattab AW. Glycogen Storage Disease Type IV. 2013 Jan 3. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK115333/  

21. World J Gastroenterol. 2007 May 14; 13(18): 2541–2553.

Published online 2007 May 14. doi:  10.3748/wjg.v13.i18.2541 PMCID: PMC4146814 Glycogen storage diseases: New perspectives Hasan Özen 

22. Glycogen branching enzyme deficiency in adult polyglucosan body disease.

Bruno C, Servidei S, Shanske S, Karpati G, Carpenter S, McKee D, Barohn RJ, Hirano M, Rifai Z, DiMauro S 

Ann Neurol. 1993;33(1):88.  

23. Adult polyglucosan body myopathy.

Goebel HH, Shin YS, Gullotta F, Yokota T, Alroy J, Voit T, Haller P, Schulz A

J Neuropathol Exp Neurol. 1992 Jan; 51(1):24-35. 

24. Ann Neurol. Author manuscript; available in PMC 2015 Feb 16.

Ann Neurol. 2012 Sep; 72(3): 433–441. doi:  10.1002/ana.23598 PMCID: PMC4329926 NIHMSID: NIHMS415710

Adult Polyglucosan Body Disease: Natural History and Key Magnetic Resonance Imaging Findings

Fanny Mochel, MD, PhD,^1,2,3,4 Raphael Schiffmann, MD,⁵ Marjan E. Steenweg, MD,⁶ Hasan O. Akman, PhD,⁷ Mary Wallace, RD,⁵ Frédéric Sedel, MD, PhD,^1,3,8 Pascal Laforêt, MD,^3,9 Richard Levy, MD, PhD,^4,10,11 J. Michael Powers, MD,¹² Sophie Demeret, MD,⁸ Thierry Maisonobe, MD,¹³ Roseline Froissart, PhD,¹⁴ Bruno Barcelos Da Nobrega, MD,¹⁵ Brent L. Fogel, MD, PhD,¹⁶ Marvin R. Natowicz, MD, PhD,¹⁷ Catherine Lubetzki, MD, PhD,^1,4,8 Alexandra Durr, MD, PhD,¹² Alexis Brice, MD,^1,2,4,8 Hanna Rosenmann, PhD,¹⁸ Varda Barash, PhD,¹⁹ Or Kakhlon, PhD,¹⁸ J. Moshe Gomori, MD,²⁰ Marjo S. van der Knaap, MD, PhD,⁶ and Alexander Lossos, MD¹⁸ 

25. PMID 8274116

Glycogen-branching enzyme deficiency leads to abnormal cardiac development: novel insights into glycogen storage disease IV.

Lee YC¹, Chang CJ, Bali D, Chen YT, Yan YT.

5. Acta Myol. 2011 Oct; 30(2): 96–102.

PMCID: PMC3235878 Progress and problems in muscle glycogenoses

S. DiMauro and R. Spiegel¹ 

6. Hum Mol Genet. 2015 Oct 15;24(20):5667-76. doi: 10.1093/hmg/ddv280. Epub 2015 Jul 21. 

7. Neuromusc. Disord. 14: 253-260, 2004. [PubMed: 15019703