Pulmonary Medicine Made Easy: May 2012

*BASICS OF VENTILATION PHYSIOLOGY:
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! Tidal volume (VT) = Vdead space (Vd) +V alveolar (VA)
! Minute ventilation (MV) = TV x RR
! VA = Vco2/Paco2 x K (constant)

*DEFINITION:
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Alveolar hypoventilation is defined as insufficient ventilation leading to an increase in PaCO2 (ie, hypercapnia). Alveolar hypoventilation is caused by several disorders that are collectively referred as hypoventilation syndromes. Alveolar hypoventilation also is a cause of hypoxemia. Thus, patients who hypoventilate may develop clinically significant hypoxemia. The presence of hypoxemia along with hypercapnia aggravates the clinical manifestations seen with hypoventilation syndromes.
Alveolar hypoventilation may be acute or chronic and may be caused by several mechanisms.

*ETIOLOGIES Of ALVEOLAR HYPOVENTILATION:
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1) Chemo sensitivities/sensors:
o Appropriate response to primary metabolic alkalosis (1mEQ HCO3 corresponds to 0.6
mmHg rise of PaCO2)
o Impaired peripheral chemo receptor (carotid bodies) response to hypoxia-s/p CEA
o Impaired central chemo receptor (midbrain and medulla) response to acidosis

2) Brain stem dysfunction (medulla central pattern generator cells):
o Stroke-thrombosis, embolic, bleed
o infiltration-neoplasm, sarcoidosis
o demyelinating disorders-MS
o Drug/toxins-narcotics, BDZ, ETOH
o Infection-encephalitis, bulbar poliomyelitis, basilar meningitis
o Primary alveolar hypoventilation

3) Spinal cord, peripheral nerves and respiratory muscles dysfunction
o Motor neuron disease-ALS, polio
o Peripheral neuropathy-phrenic nerve compression, resection, GBS,
o Neuromuscular junction-MG, ELS,
o myopathies-drugs, dystrophies, hypothyroidism, DM/PM

4) Chest wall dysfunction: stiff chest wall imposes large elastic load on the lung, increase work of
breathing, increased dead space ventilation (tachypneic with small TV breaths)
o obesity hypoventilation (Pickwinian syndrome)
o kyphoscoliosis
o fibrothorax
o post-thoracoplasty
o ankylosing spondylitis

5) Lung and airways dysfunction
o COPD-increased dead space ventilation
o Upper airway obstruction
o Cystic fibrosis
o Obstructive sleep apnea

*REASONALBLE DIAGNOSITIC APPROACH TO A PATIENT:
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- Check a TSH
- ABG: elevated A-a gradient is seen in disorders of chest wall, lung or airways; normal A-a
gradient with central or neurological disorders
- PFT’s: restrictive pattern is seen with chest wall disorders, obstructive with airway disease, PI/PE
max are decreased with neuromuscular disorders
- Sleep studies: central apneas seen with central disorders, obstructive apneas with OSA, note all
disorders will worsen with sleep
- If above studies are normal, tests of respiratory control can be performed. Pt is stimulated by
hypoxia and hypercapnea and ventilatory responses are recorded.
- Consider: diaphragmatic EMG to evaluate phrenic nerve, MRI head for brainstem mass

*COMPLICATIONS OF CHRONIC ALVEOLAR HYPOVENTILATION:
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- Decreased alveolar ventilation results hypercapnea, and hypoxemia.
- Sleep accentuates these abnormalities because of decreased respiratory drive
- Physiologic consequences include increased erythropoesis, metabolic alkalosis, pulmonary
vasoconstriction, cerebral vasodilatation, impaired sleep
- Clinically, patients present with polycythemia, pulmonary hypertension, cor pulmonale, morning
headache, fatigue, daytime somnolence and poor sleep

Septic Pulmonary Emboli

.General Considerations:

■Age: Majority <40 years

■Predisposed

IV drug abusers

Alcoholism

Immunodeficiency

CHD

Dermal infection (cellulitis, carbuncles)

■Sources

Tricuspid valve endocarditis

Most common cause in IV drug abusers

Pelvic thrombophlebitis

Infected venous catheter or pacemaker wire

Arteriovenous shunts for hemodialysis

Drug abuse producing septic thrombophlebitis (eg, heroin addicts)

Peritonsillar abscess

Osteomyelitis

■Organism

S. aureus

Streptococcus

Clinical Findings

■Sepsis

■Cough

■Dyspnea

■Hemoptysis: Sometimes massive

■Chest pain

■Shaking chills

■High fever

■Severe sinus tachycardia

■Location: Predilection for lung bases

Imaging Findings

■Multiple round or wedge-shaped densities

■Cavitation

Frequent

Usually thin-walled

■Migratory: Old ones clear and new ones arise

■Pleural effusion is rare

■Hilar and mediastinal adenopathy can occur

■CT findings

Multiple peripheral parenchymal nodules

Cavitation or air bronchogram in more than 89% : Cavities are thin-walled and may have no fluid level

Wedge-shaped subpleural lesion with apex of lesion directed toward pulmonary hilum (50%)

Feeding vessel sign = pulmonary artery leading to nodule (67%)

Differential Diagnosis of Small Cavitary Lung Lesions

Septic emboli

Rheumatoid nodules

Squamous or transitional cell metastases

Necrotizing Granulomatosis

Complications

■Empyema (39%)

Lipoid Pneumonia

Lipoid Pneumonia

Exogenous accumulation of fat in the lung most often from mineral oil:
Older people who are constipated, have a swallowing disorder 2° neurologic disease
In infants with feeding difficulties
In the past, could be from oily nose drops
Accumulation of fat in the lung may also occur from endogenous sources such as fat embolism, alveolar proteinosis lipid storage diseases
Animal fatty acids (like fat embolus) produces hemorrhagic bronchopneumonia
Mineral oil produces a giant cell foreign body reaction
Starts as an alveolar infiltrate
Moves to thicken interstitial septa, then
Into macrophages enlarging lymphatics
Finally produces a fibrosing reaction

X-ray

Usually lower lobes with predilection for the right
Alveolar consolidation, may be well-circumscribed
May present as a peripheral mass with fuzzy or distinct margins simulating BrCa

Clinical

Usually asymptomatic

Diagnosis

Best method of DX is direct Bx
Fat-laden macrophages are non-specific since they can be found in sputum of normals as well

Bullous Disease of the Lung

.Definition:

o Thin-walled–less than 1 mm
o Air-filled space
o Contained within the lung
o 1 cm in size when distended
o Walls may be formed by pleura, septa, or compressed lung tissue

Other air-containing structures:

1.Pneumatocoele:
Thin-walled (< 1mm), gas-filled space in the lung developing in association with acute pneumonia, such as staph, and frequently transient

2.Cavity: Gas-containing space in the lung having a wall > 1 mm thick

3.Cyst: Thin-walled, air- or fluid-filled, with a wall that contains respiratory epithelium, cartilage, smooth muscle and glands

4.Bleb: Intrapleural cystic space

Bulla terminology:

o One of them is a bulla
o Two or more of them are bullae (pronounced bully)
o Diseases which contain bullae are bullous diseases

General considerations:

o Enlarge progressively over a period of months to years
o Most are associated with emphysema
o May become infected or lead to pneumothorax

Primary Bullous Disease:

o Familial occurrence
o Increased incidence in Marfan's and Ehlers-Danlos
o Unlike the bullae associated with emphysema, there is usually no airway obstruction and there is normal parenchyma between bullae

Types of Bullae:

Type 1
§ Originate in a subpleural location usually in upper part of lung
§ Narrow neck
§ Produce passive atelectasis of adjacent lung tissue
§ Paraseptal emphysema

Type 2
§ Superficial in location
§ Very broad neck
§ Anterior edge of upper and middle lobes and along diaphragm
§ Contain blood vessels and strands of partially destroyed lung
§ Spontaneous pneumothorax

Type 3
§ Lie deep within lung substance
§ Like type 2, contain residual strands of lung tissue
§ Affect upper and lower lobes with same frequency

Imaging findings:

o Seen more in upper lobes
o Thin-walled, sharply demarcated areas containing no visible blood vessels on conventional radiography
o Only portion of wall is usually seen on conventional radiography
o They tend to trap air: May become larger on expiration
o Bullae may become so large as to render the remaining normal lung almost invisible, pancaked atop the hemidiaphragm = vanishing lung syndrome

Signs of an infected bulla:

o Air-fluid level

o Differentiation from lung abscess

1. Bulla contains less fluid

2. Much thinner wall

3.No surrounding pneumonitis

4.Patients less sick with infected bulla

o Clearing may take weeks to months

Bullous disease and spontaneous pneumothorax:

o Commonly occurs with small bulla affecting lung apices
o May be difficult to differentiate large bulla from pneumothorax
o Edge of a pneumothorax will usually parallel the chest wall curvature whereas edge of a bulla frequently curves inwards away from the chest wall
o CT may help

Clinical findings:

o 1° bullous disease usually has no symptoms
o When large, surgical removal may be performed
o Patients with chronic obstructive pulmonary disease tend to show little difference clinically or functionally with or without bullae

Differentials in Chest

Acute Alveolar Infiltrate:
- Pulmonary Edema
- Pneumonia
- Hemorrhage
- Aspiration

Chronic Alveolar Disease:
- Alveolar cell carcinoma
- Alveolar Sarcoidosis
- Alveolar Protienosis
- Lymphoma

Anterior Mediastinal Masses:
- Thymoma
- Thrytoid (retrosternal)
- Teratoma
- Lymphoma

Middle Mediastinal Masses:
- Lymphadenopathy
- Aortic Aneurysm
- Esophageal Duplication cyst
- Bronchial cyst

Posterior Mediastinal Masses:
- Neurogenic Tumors
- Lymphadenopathy
- Extramedullary Hematopiesis

Opacified Hemithorax:
- Atelectasis
- Effusion
- Pneumonia
- Post-pneumonectomy

Bibasilar Interstitial Disease:
- Bronchiectasis
- DIP
- Asbestosis
- Sarcoidosis
- Aspiration
- Scleroderma

Chronic Interstitial Disease:
- Pneumoconiosis
- Interstitial Pneumonia
- Granulomatous disease
- Collagen Vascular Disease
- Idipathic Fibrosis
- Neoplastic disease

Micronodular Lung Disease:
- Miliary TB
- Pneumoconiosis
- Sarcoidosis
- Metastasis

Cavitary Lung Lesions:
C Cancer (squamous cell carcinoma, melanoma, sarcoma mets)
A Autoimmune (Wegener's granulomatosis, rheumatoid lung)
V Vascular (ie bland or septic emboli)
I Infection (TB, fungal (coccidioidomycosis, aspergillosis), bacterial (Staph, strep, Klebsiella))
T Trauma
Y Youth (ie congenital: bronchogenic cyst, sequestration)

Large Cavitary Lesions:
- TB
- Cancer Lung
- Abscess

Small Cavitary Lung Nodules:
- TB
- Rheumatoid nodules
- Septic Emboli
- Transitional or Squamous cell metastasis
- Wegner's Granulomatosis

Multiple Lung Nodules:
- TB
- Wegner's Granulomatosis
- Rheumatoid nodules
- AVMs
- Metastasis
- Septic Emboli

Masses with Airbronchograms:
- Alveolar Cell carcinoma
- Lymphoma
- Pseudo-lymphoma

Small Calcifications in Lungs:
- Alveolar Microlithiasis
- Silicosis (upper)
- Histoplasmosis
- Varicella Pneumonia (healed)

Cavities Containing Masses:
- Aspergillomas
- Hydatid Cyst
- Carcinoma

Masses that Cavitate:
- Metastatic masses
- Wegner's G
- Rheumatoid
- Septic Emboli

Infiltrates with Effusion:
- TB
- Staph Pneumonia
- Strept Pneumonia
- Pulmonary Infarction

Cystic Lung Lesions:
L Lymphangioleiomyomatosis, Lymphocytic interstitial pneumonia, Langerhans Cell Histiocytosis
I Infection (TB, Staphylococcus, PCP)
S Sarcoid
T Tuberous sclerosis

Lateral Decubitus Film Uses

Lateral decubitus Film:

1- Detect small areas of air at uppermost pleural space

2- Detect small areas of dependent Pleural Fluid

3- Measure size and mobility of fluid collection

4- Accessible with sampling needle (>1 cm size)

5- Uncover Lung tissue obscured by Pleural Fluid

6- Place side of interest up

7- Mobility of mediastinal or pleural masses

8- Assess mobility of solids and fluids within cavities

9- Assist with maximizing inspiration of uppermost lung

10- the dependant lung should increase in density due to atelectasis from the weight of the mediastinum putting pressure on it. Failure to do so indicates air trapping.

Adenosine Deaminase in Pleural Effusion

SOME FACTS ABOUT ADA

■ADA is an enzyme in purine salvage pathway that catalyzes the conversion of adenosine and deoxyadenosine to inosine and deoxyinosine.

■Abundant in activated T lymphocytes.

■An ADA level >70 IU/L is highly suggestive of TB while a level < 40 IU/L virtually excludes the diagnosis of tuberculosis.

■Meta-analysis of 40 studies from 1966 to 1999 showed the ADA sensitivity to vary between 47.1% to 100% and specificity between 0 to 100%

■Specificity increases when lymphocyte to neutrophil ratio in pleural fluid (>0.75) is considered in conjugation with an ADA concentration >50 IU/L

■In low prevalence setting (i.e. <1%) positive predictive value may be as low as 15% however negative predictive value increases.

■In high prevalence of tuberculosis, ADA measurement is inexpensive, minimally invasive, rapid and readily accessible test that has sensitivity and specificity of 95% and 90% respectively.

■Elevated ADA in lymphocyte rich pleural fluid has been reported in other diseases, such as rheumatoid arthritis, bronchoalveolar carcinoma, mesothelioma, mycoplasma and chlamydia pneumonia, psittacosis, paragonimiasis, infectious mononucleosis, brucellosis, mediterrianes fever, histoplasmosis, cocoidiodomycosis and in most patient with empyema.

■Two isoenzymes ADA1 and ADA2

■ADA1 is found in all cells with the highest activity observed in lymphocytes and monocytes.

■ADA2 isoenzyme is predominantly found in monocytes/macrophages.

■ADA2 isoenzyme is primarily responsible for increase ADA activity in TB pleural effusion with a median contribution of 88%

■Pleural effusions with high ADA level and ADA1/total ADA ratio <0.45 makes the diagnosis of TB highly likely.

■In immune compromised person ADA hold similar significance

Pulmonary Complications of Sickle Cell Anemia

Sickle cell disease (SCD) encompasses a group of hemoglobinopathies characterized by a single amino acid substitution in the beta globin chain. Hemoglobin S results from the substitution of a valine for glutamic acid as the sixth amino acid of the beta globin chain. The resulting hemoglobin tetramer (alpha2/betaS2) is poorly soluble when deoxygenated. This deoxygenated hemoglobin polymerizes into sheets of elongated rope-like fibers, causing a marked decrease in red cell deformability and distortion of the cell into the classic crescent or sickle shape. The most frequently occurring form of SCD is sickle cell anemia (HbSS). Acute and chronic pulmonary complications occur frequently in patients with SCD, and represent the most common cause of death from SCD in adult.

The common pulmonary complications are:

1.Infection

2.Embolic phenomena due to bone marrow infarction and fat emboli

3.Infarction caused by in-situ thrombosis

4.Rib and sternal infarctions

5.Pulmonary edema

Acute chest syndrome — The acute chest syndrome (ACS) is the most common form of acute pulmonary disease in patients with SCD.

Signs and symptoms are:

■Presence of a new pulmonary infiltrate

■Chest pain

■Temperature >38.5ºC

■Tachypnea, wheezing, or cough

Etiology of ACS is unclear.
Unknown cause — 46 %
Pulmonary infarction — 16 %
Fat embolism, with or without infection — 9 %
Chlamydophila (formerly Chlamydia) pneumoniae infection — 7 %
Mycoplasma pneumoniae infection — 7 %
Viral infection — 6 %
Mixed infections — 4 %
Other pathogens — 1%

Clinicl findings following symptoms were present at the time of diagnosis of ACS
Fever — 80 %
Cough — 62 %
Tachypnea — 45 %
Chest pain — 44 %
Shortness of breath — 41 %
Arm and leg pain — 37 %
Abdominal pain — 35%
Rib or sternal pain — 21 %
Wheezing — 13 %

Management — The acute treatment of ACS is primarily supportive and is based upon the potential etiology.

Pneumonia — Patients with SCD are predisposed to develop pneumonia due to impaired host defenses, including loss of antibody protection (in the setting of auto-splenectomy), altered phagocytic function, and defective opsonization

Fat and bone marrow embolism — Bone marrow infarction resulting from microvascular occlusion is the probable pathogenic mechanism common to the initiation of both fat and bone marrow embolism in patients with SCD . Patients with SCD and pulmonary fat embolism (PFE) frequently have mental status changes, thrombocytopenia, falling hematocrit, and severe hypoxemia, a clinical presentation similar to that in patients in whom PFE develops following the fracture of long bones
Treatment options
Exchange transfusion
Plasma infusions
Glucocorticoids

Venous thromboembolism — Autopsy data of the lungs of patients with SCD reveal fibrin thromboembolism in larger arteries with or without infarction, and extensive thrombosis in smaller arteries

Sickle cell chronic lung disease — SCCLD may begin to develop as early as the second decade of life. Pulmonary dysfunction rapidly progresses, with death occurring within seven years of diagnosis Patients characteristically progress through four clinical stages based upon physiologic and radiographic data and symptoms
Stage 1 - recurrent chest pain and cough, mild reductions in forced vital capacity (FVC) and total lung capacity (TLC), normal oxygen saturation, and near normal chest radiographs with slightly increased interstitial markings.
Stage 2 - greater pain than stage 1, moderate reductions in FVC and TLC, normal oxygen saturation, and diffuse interstitial fibrosis (all lobes on chest radiograph).
Stage 3 - severe, crushing chest pain, hypoxemia during stable periods (PO2 approximately 70 mmHg), severe reductions in FVC and TLC, and pulmonary fibrosis on chest imaging.
Stage 4 - prolonged chest pain, fixed dyspnea, hypoxemia at rest, severe pulmonary fibrosis on chest radiograph, and elevated pulmonary artery pressure at rest

Obstructive sleep apnea — Upper airway obstruction during sleep due to adenoid and tonsillar enlargement has been found in up to one-third of children with SCD.

Alterations in baseline pulmonary function —Many different parameters of pulmonary function are altered in patients with sickle cell lung disease.
As examples: Total lung capacity and vital capacity may be reduced. Even when corrected for anemia, the diffusing capacity for carbonmonoxide (DLCO) is abnormally low.
Arterial oxygen saturation (SaO2) is reduced.
The alveolar-arterial difference is widened both at rest and with exercise
Mild to moderate airflow obstruction may be present, particularly among patients with recurrent episodes of acute chest syndrome.

Pulmonary hypertension in patients with SCD is 20 to 40 percent

Polyarteritis Nodosa

.■Systemic necrotizing inflammation of medium-sized and small muscular arteries: More common in adult males

■Spares the arterioles, capillaries, venules and glomeruli

■Associated with hepatitis B antigenemia

■Signs and symptoms

Abdominal painSystemic hypertensionAnorexia and weight lossAbdominal distentionHematemesis, melenaJaundicePainless hematuriaPeripheral neuropathyTender subcutaneous nodulesGangrene of fingers and toes

■Kidney (most frequently affected): 85%

Multiple intrarenal aneurysms Multiple aneurysms of renal vessels in Polyarteritis-Aneurysms may thrombose and disappear-Appear in new locations-Multiple small cortical infarcts-Angiographic findings1.1-5 mm saccular aneurysms of small and medium-sized arteries in 60-75% of cases

2.Secondary to necrosis of internal elastic lamina

3.Luminal irregularities and stenoses

4.Arterial occlusions and small tissue infarcts

■Lung (70% of cases)

Findings are variable and rarely characteristic enough to allow diagnosisMost characteristic pattern is fleeting, patchy consolidation identical to Loeffler'sPericardial effusionPleural effusionDiscoid atelectasisNodules which may cavitatePatchy consolidation

■Liver: affected 66% of cases

■Treatment : Corticosteroids (50% 5 year survival)

Idiopathic Pulmonary Hemorrhage & Goodpasture's Syndrome

• Both are characterized by repeated episodes of pulmonary hemorrhage
• Both produce iron-deficiency anemia and both can produce pulmonary insufficiency
• Pathology
            • Hemorrhage is typically confined to peripheral airspaces
            • Diffuse interstitial fibrosis, hemosiderosis are common
            • Vasculitis doesn't always occur even though these are autoimmune diseases
• Hemoptysis more copious in IPH
• Prognosis for both diseases is grave – both are treated with steroids and cytotoxic agents

Idiopathic pulmonary hemorrhage
• Occurs most commonly in children under the age of ten
• When it occurs in adults, it is twice as common in men
• Anti-glomerular basement membrane antibody should be absent (unlike Goodpasture’s)

Goodpasture’s syndrome
• Goodpasture’s includes renal disease
• Renal lesion is glomerulonephritis
• It is a disease of young adults
• Most are men
• Autoimmune etiology
• Both lung and renal pathology believed 2° to anti-glomerular basement membrane antibody cross reacting with lung basement membrane
X-ray
• Identical changes in both diseases
• Early in the disease, it is alveolar in nature, more prominent at the bases and perihilar regions — simulates pulmonary edema
• Within 2-3 days, the blood is absorbed in to the interstitium and the pattern changes to interstitial reticular
• By about 10 days, the reticular disease disappears
• With repeated bleeds, there is hemosiderin deposit in the lungs and progressive pulmonary fibrosis occurs
• Once this occurs, the new hemorrhage is superimposed on the old interstitial disease, so the reticular pattern remains rather than disappears when the blood is absorbed
• May have pulmonary hypertension
• May have hilar adenopathy

Wegner's Granulomatosis

General

Male:female ratio of 2:1
Peak in 40s
Autoimmune disease characterized by necrotizing granulomas and angiitis
Diagnosis is made by lung or kidney biopsy
Death comes from renal failure or respiratory failure
Treated with steroids and cytotoxic drugs

Respiratory Tract (100% involved)
Upper respiratory tract

Mucosal thickening in paranasal sinuses
Bone and cartilage destruction

Lung

Multiple nodules of varying sizes, especially at bases
Cavitate frequently (50%)
Masses wax and wane
Pleural effusion (25%)
Alveolar infiltrate occasionally

Other Organs

Urinary tract:focal glomerulonephritis (50%)
Joints:migratory polyarthropathy (56%)
Skin:inflammatory skin lesions (44%)
Eyes and ears:proptosis and otitis media (29%)
Heart and pericardium: myocardial infarction (28%)
CNS: neuritis (22%)

Symptoms

Rhinorrhea
Sinusitis
Epistaxis
Cough with hemoptysis

Midline Lethal Granuloma

Variant of Wegener’s consisting of mutilating granulomatosis and neoplastic lesions limited to nose and paranasal sinuses

INITIAL TREATMENT FOR WG:

We recommend combination cyclophosphamide-glucocorticoid therapy in the initial treatment of most patients with WG or MPA.

- This is particularly indicated in those with life-threatening disease, including patients with a serum creatinine concentration greater than 2.0 mg/dL (177 µmol/L), pulmonary involvement resulting in hypoxemia, CNS disease, and/or bowel perforation/infarction.

- Either daily oral or monthly intravenous cyclophosphamide is effective in inducing remissions in most patients with WG or MPA. The critical point in the management of patients on cyclophosphamide is close clinical follow-up and regular laboratory testing to avoid neutropenia.

a) Daily oral cyclophosphamide-glucocorticoid regimen

*Cyclophosphamide is given orally in a dose of 1.5 to 2 mg/kg per day. Therapy is continued until a stable remission is induced, which is usually achieved within three to six months. The white blood cell count (WBC) must be closely monitored and the cyclophosphamide dose adjusted to avoid severe leukopenia (WBC should remain above 3000/mm3 and absolute neutrophil count above 1500/mm3).

*When initiating glucocorticoid therapy, there is disagreement among experts and among the authors as to whether therapy should be begun with pulse methylprednisolone (7 to 15 mg/kg to a maximum dose of 500 to 1000 mg/day for three days) in all patients or only in those with necrotizing or crescentic glomerulonephritis or more severe respiratory disease.

Oral glucocorticoid therapy, either from day 1 or day 4 if pulse methylprednisolone is given, typically consists of 1 mg/kg per day (maximum of 60 to 80 mg/day) of oral prednisone (or its equivalent). A variety of prednisone tapering schemes have been employed. In general, the initial high dose should be continued for two to four weeks. If significant improvement is observed at this time, the dose of prednisone may be tapered slowly, with the goal of reaching 20 mg of prednisone per day by the end of two months and an overall glucocorticoid course of between six and nine months. Alternate day glucocorticoid regimens, once recommended in WG, are not generally employed now.

b) Monthly intravenous cyclophosphamide — An alternative to daily oral cyclophosphamide is intravenous monthly pulse cyclophosphamide therapy. Monthly cyclophosphamide is typically administered in doses of 0.5 to 1.0 g/m2 body surface area for three to six months, until a stable remission is induced. Prednisone is given concurrently with monthly intravenous cyclophosphamide, using similar regimens as with daily oral cyclophosphamide.

- Prophylaxis — Given the toxicity of cyclophosphamide, prophylactic therapy should be provided for Pneumocystis pneumonia usually with trimethoprim sulfamethoxazole. Trimethoprim-sulfamethoxazole should not be used by patients also taking methotrexate.
Other prophylactic measures are directed at preventing bladder and gonadal toxicity.
Given the toxicities of prolonged glucocorticoid use, prophylactic treatments should be provided for oropharyngeal fungal infections (nystatin), gastritis (H2 blocker or proton pump inhibitor for patients at increased risk for gastrointestinal bleeding), and bone loss (calcium and vitamin D or bisphosphonate).

Methotrexate — A methotrexate-based regimen, in conjunction with glucocorticoids, is an option in patients with mild disease . This primarily includes those with pulmonary nodules or infiltrates without respiratory compromise, and/or ocular disease. Although this regimen can be used to treat patients with glomerulonephritis and normal or near-normal serum creatinine, it is not recommended given the high rate of relapse. If the regimen is used, patients require close follow-up.
A methotrexate-based regimen may be particularly attractive in such patients who have limited bone marrow reserve from past cyclophosphamide use, a history of cyclophosphamide-induced bladder injury, or concerns relating to major cyclophosphamide toxicity. Methotrexate should not be administered to patients with a serum creatinine concentration above 2.0 mg/dL (177 µmol/L) given the increased risk of toxicity in those with renal dysfunction, and patients should not receive concurrent trimethoprim-sulfamethoxazole.
One regimen consists of oral methotrexate at an initial dose of 0.3 mg/kg (but not exceeding 15 mg) once per week, with increases of 2.5 mg each week to a maximum dose of 20 to 25 mg/week [27] . Since methotrexate is a structural analogue of folic acid that can competitively inhibit the binding of dihydrofolic acid (FH2) to the enzyme dihydrofolate reductase (DHFR), folic acid (1 to 2 mg/day) or folinic acid (2.5 to 5 mg per week, 24 hours after methotrexate) should be given concurrently to reduce potential toxicity.

Glucocorticoids are administered concurrently with methotrexate. The dosing regimen for prednisone is the same as that previously described for prednisone when used with daily oral cyclophosphamide therapy.

Plasma exchange — We suggest plasma exchange in selected groups of patients with WG or MPA, given the high morbidity and mortality associated with these specific clinical settings: Patients with anti-GBM antibodies as well as ANC Patients with severe pulmonary hemorrhage on presentation (as defined radiographically or by arterial oxygen saturation) or those with worsening pulmonary hemorrhage despite the combination of high-dose glucocorticoids and cyclophosphamide Patients who have advanced renal dysfunction at presentation, as defined by a serum creatinine level above 5.8 mg/dL (500 µmol/L) and/or dialysis dependence
The potential morbidity associated with plasma exchange must be strongly considered before pursuing this modality given the uncertainty regarding its benefits.
The method and duration of plasma exchange vary with the response to therapy and the clinical presentation.

Among patients with ANCA-associated vasculitis who present with advanced renal dysfunction, we suggest seven sessions of plasma exchange over two weeks (60 mL/kg at each session). A more prolonged regimen is used in patients with anti-GBM disease.
In general, albumin can be used as the replacement fluid. However, if the patient has had a recent renal biopsy or has pulmonary hemorrhage, then one to two liters of fresh frozen plasma should be substituted for albumin at the end of the procedure to reverse pheresis-induced depletion of coagulation factors.
If a severe infection develops in the setting of plasma exchange, a single infusion of intravenous immune globulin (100 to 400 mg/kg) can be given to partially replenish antibody levels.