Chapter 46: Rheumatologic and Inflammatory Conditions in the ICU

According to the most recent literature, about a third of rheumatologic patients admitted to the hospital will require admission in an intensive care unit (ICU). Their in-ICU mortality can be as high as 55% and can reach 79% in the systemic lupus erythematous (SLE) population. Such a severe life threatening decompensation may be caused by multiorgan system failure related to disease flare or by the complications of immunosuppressive state or therapy, such as infection.^{1,2,3,4,5,6,7,8,9,10,11,12,13,14}

Severe sepsis and septic shock represent in fact the primary reason for ICU admission in about half of the rheumatologic patients. It is the first cause of mortality in SLE patients, therefore, it is crucial to recognize and aggressively treat any infectious process before attempting to achieve diseases control with immunosuppressive therapy.

An increasing number of patients will be recognized ex novo to have a rheumatologic condition during their ICU stay. Such diagnosis can be quite challenging for the intensivist and usually require a multidisciplinary approach.

Few diagnostic tests, that is, autoantibodies, are confirmatory and when negative do not rule out the disease if clinical criteria are met. On the other end of the spectrum, positive autoantibodies can be found in healthy individuals and in extrarheumatologic conditions (Table 46–1). The clinical manifestations of autoimmune diseases itself can be very heterogeneous and virtually all organ systems can be affected.

The most common adult rheumatologic disease encountered by the intensivist are in order of frequency, according to the most recent literature, SLE, rheumatoid arthritis (RA), systemic vasculitis, and systemic sclerosis (SS).

Acute respiratory failure appears to be the most common indication for ICU admission. It remains difficult to estimate from various studies whether related to disease flare involving the respiratory system or to primary pulmonary infectious process or both.

Severe Sepsis

Acute respiratory failure due to pneumonia appears to be the most common reason for ICU admission. Chronic inflammatory process and immunosuppressant therapy make rheumatologic patients extremely susceptible to severe infections. Fever and leukocytosis may not be present.

The most common microorganisms involved are the typical bacterial pathogens, therefore treatment for community or hospital acquired pneumonia should not be delayed. Cases of nonresolving pneumonia must raise suspicion for atypical bacterial infections, reactivation of tuberculosis, disseminated fungal disease (histoplasmosis, cryptococcosis, and aspergillus spp.), listeriosis, and Pneumocystis pneumonia.

Effort should be made to collect all the appropriate body fluids and specimens before initiation of antibiotics treatment. Bronchoalveolar lavage (BAL) should be considered early on in the course of the disease.

Pneumocystis pneumonia prophylaxis should be considered for patient on immunosuppressant agents.

Airway Involvement

Inflammation within the airway, obstruction from inflammation, ankylosis of the cricoarytenoid joints or cervical spine can represent challenging airways for the intensivist.

Conditions associated with airway involvement include RA, granulomatosis with polyangiitis (GPA, former Wegener granulomatosis), relapsing polychondritis and SLE.

Occasionally obstruction caused by angioedema may be seen in its acquired form in lupus patients. Subglottid stenosis can be present in about 10% to 20% of patients with GPA. Relapsing polychondritis of both small and large airways can cause upper or lower airway obstruction due to recurrent cartilage inflammation and destruction. Patients with advanced cutaneous scleroderma may represent difficult airway if mouth opening is narrowed.

Upper airway problems may arise especially in patients with RA and ankylosing spondylitis if airway needs to be secured.

Atlantoaxial subluxation (C1-C2) may be present in RA male patients particularly in those with severe peripheral joint deformities, long disease duration and neck pain. Patients undergoing elective surgery should have cervical radiologic evaluation since subluxation can be asymptomatic and neck manipulation during intubation may be proven to be fatal. In emergent situations, fiberoptic intubation will be the preferred option.

Pulmonary Disease

Respiratory insufficiency is the leading causes of ICU admission. Its manifestation may be expression of autoimmune flare or infection. Interstitial lung disease (ILD), pleuritis, pleural effusion, pulmonary hemorrhage, and embolism can all be encountered in critically ill rheumatologic patients.

RA patients tend to have an increased rate of ILD, cryptogenic organizing pneumonia, obliterative bronchiolitis, and pleural involvement. Pulmonary hemorrhage seems more prevalent in systemic vasculitis and when associated with SLE.

Among all the rheumatologic diseases SS seems to have the highest prevalence (80%) of pulmonary involvement. ILD (being the nonspecific interstitial pneumonia the most common) and pulmonary arterial hypertension are the most common features and both can coexist. These patients should be screened before symptoms appear since early intervention can slow the disease progression. Doppler echocardiography and right heart catheterization are necessary to estimate pulmonary arterial hypertension. Further lung injury from recurrent aspiration is frequently experienced in scleroderma patients due to an incontinent gastroesophageal sphincter.

Sjogren syndrome (SJ) and polymyositis-dermatomyositis also share a high rate of pulmonary involvement as shown in Table 46–2.

Pleural involvement occurs frequently in RA and SLE patients. The pleural fluid exam is an exudates with low pH, low glucose with a lymphocytic predominance. The level of rheumatoid factor in the pleural fluid parallels that in the serum. Recurrent effusions may require a more definitive treatment (pleurodesis).

Pulmonary embolism and deep vein thrombosis may be the primary manifestation of an underlying prothrombotic state caused by a rheumatologic condition. Lifelong prophylactic anticoagulation is required since new evidence from population-based studies show a 2 to 3 fold increase of thromboembolic phenomena in these patients.

Loss of anticoagulants factor due to concomitant renal impairment can also contribute to a prothrombotic state.

Drug-induced lung toxicity, that is, methotrexate is usually a diagnosis of exclusion.

The general evaluation of pulmonary involvement should include a chest X-ray (CXR), oftentimes not sensitive and a high resolution computed tomography (CT) of the chest. The latter may show pulmonary nodules, ground glass opacity as well as reticular pattern and honeycombing. BAL can help in differentiating between exacerbation of rheumatic disease, infection, drug-induced respiratory failure and alveolar hemorrhage. BAL and lung biopsy can aid the diagnosis but both have no role in prognostication.

Aggressive immunosuppressive therapy is warranted to decrease pulmonary inflammation and evolution into acute lung injury as well as multiorgan involvement.

Cardiovascular Disease

Pericardial involvement may affect 12% to 48 % of patients with lupus and as high as 35% in patients with RA. Acute pericarditis may rarely evolve into cardiac tamponade but its progression into chronicity may cause restrictive cardiomyopathy requiring surgical intervention.

Rheumatoid nodules can involve the myocardium and the heart valves causing embolic phenomena and conduction disturbances (RA, SS, and its variant CREST). Myocarditis in lupus and polymyositis-dermatomyositis patients may lead to overt heart failure.

Libman Sacks endocarditis occurs in about 10% of SLE patients. Its fibrinoid vegetations can cause severe valvular regurgitation (mitral and aortic valve most commonly) and thromboembolic phenomena especially if antiphospholipid (APL) syndrome is associated.

Rheumatologic patients are at high risk of acute coronary syndromes due to premature atherosclerosis compared to age-match population. Within the rheumatologic diseases, patients affected by Kawasaki and systemic vasculitis are at the highest risk due to the chronic inflammation of coronary arteries and associated arteritis.

Gatrointestinal Disease

Gastrointestinal hemorrhage is frequently encountered in patients treated with corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). Stress ulcers may provoke brisk bleeding if coagulopathy and thrombocytopenia are associated.

Henoch–Schonlein purpura, SS, necrotizing vasculitis may all cause bleeding from ulceration of small vessels of small bowel or colonic mucosa.

Intestinal ischemia may result as a complication of panarteritis nodosa, RA, SLE, and vasculitides, in general. The clinical manifestation depends on the size and location of the vessel involved. Occasionally profuse bleeding, ulceration with perforation can be seen.

Renal Involvement

Renal involvement occurs in roughly 30% of the overall rheumatologic patients. Lupus nephritis remains the most feared complication of the disease and renal involvement can be detected in as high as 90% of patients before any overt clinical manifestations.

The spectrum of the glomerular involvement varies from minimal to advanced sclerosis. Urine analysis will show proteinuria more than 0.5 g/24 hours and red blood cell cast. Complement levels including C3 and C4 are decreased. Hypertensive crisis can be also present.

Renal biopsy should not be delayed since it can provide diagnosis, staging and therefore treatment. Aggressive immunosuppressive treatment is warranted for advanced stage of glomerulonephritis (GN, staged from I to V, being the III stage usually the initial time for treatment) to prevent further progression of injury and achieve remission. Treatment includes pulse steroids combined with IV or oral cyclophosphamide with possible mycophenolate and cyclosporine in case of refractory response. Occasionally plasma exchange may be instituted for rapid progressive GN. Some patient will recover while some will progress to end stage renal disease requiring dialysis. Renal transplant can be successful if good control of the active disease is achieved.

Scleroderma renal crisis occurs in about 15% of patient with SS. It is a medical emergency presenting with abrupt onset of hypertension and acute renal failure. It can precede the diagnosis of SS. Multisystem involvement with hypertensive encephalopathy, visual disturbances and seizure, pulmonary edema, myocarditis, microangiopathic anemia and thrombocytopenia may be all present. Urine analysis shows granular cast, mild proteinuria and hematuria.

Management includes early treatment with ACE inhibitor such as captopril and lisinopril titrate to decrease blood pressure while avoiding hypoperfusion. Steroids are generally avoided as they are linked to possible risk factor for the development of renal crisis.

Active RA can cause late stage amyloid nephropathy. NSAID, gold and penicillamine can also be responsible for nephritic disease.

Central Nervous System Disease

Primary angiitis of the central nervous system (PACNS), lupus, polyarteritis nodosa (PAN), giant cell arteritis (GCA), and SJ comprise the majority of autoimmune conditions associated with central nervous system (CNS) vasculitis. Patients with primary angiitis will lack the manifestations and the positive inflammatory markers of systemic vasculitis. Symptoms can range from severe headache, seizure, stroke, cognitive impairment, psychosis.

Lupus psychosis is a common manifestation of SLE. Antipsychotic and control of active disease are the treatment of choice. Steroid use may confound as well as precipitate the clinical picture. Lumbar puncture may show mild elevated white blood cell with predominance of lymphocytes, elevated protein and low glucose.

Cerebral venous thrombosis can be seen in patient affected by APS either primary or secondary to lupus.

Headache, diplopia, and stroke in an elderly woman with elevated ESR should raise suspicion for GCA, although a normal ESR does not exclude it. Symmetric stiffness and proximal muscle pain may be expression of the frequently associated polymyalgia rheumatica. Infections and malignancy of the CNS should be ruled out first. Lumbar puncture, brain CT, cerebral magnetic resonance imaging (MRI), and angiographic studies should be performed. Angiogram may reveal arterial stenosis, occlusion, dilatation, or vessel beading.

Hematologic Disorder

A prothrombotic state and anemia of chronic disease are usually present in patient with rheumatologic disease. Microangiopathic anemia, thrombocytopenia and leukopenia may also represent the manifestation of a disease flare that scatters autoantibodies against the hematologic series. Suppressed bone marrow function may also develop from immunosuppressive therapy.

Leukopenia is a clinical defining feature of SLE and is seen in patients with RA complicated by Felty syndrome. Thrombotic thrombocytopenic purpura (TTP) is frequently associated with pediatric SLE. APS is an autoimmune condition characterized by antibodies against phospholipids binding plasma proteins and is clinically manifested by arterial or venous thrombosis. It can occur as a primary condition or associated with other rheumatologic diseases, usually SLE. The affected organ and the clinical manifestation depend on the vessel involved and may manifest as focal neurologic deficit, transverse myelitis, seizure, pulmonary embolism, intra-alveolar hemorrhage, valvular disease, coronary thrombosis, recurrent miscarriages. A catastrophic APS is defined as a wide spread small vessel thrombosis with multiorgan failure. Mortality rate can reach up to 50%. Treatment with anticoagulation, high dose pulse glucocorticoids and plasma exchange with or without IVIG has been associated with 50% to 80% recovery rate.

Coagulation abnormality caused by autoantibodies anticlotting factors may be manifest as disseminated intravascular thrombosis, bleeding or both. Autoantibody antifactor VIII is the most common autoimmune coagulation disorder seen in SLE and RA. Cessation of bleeding will respond to porcine factor VIII which is antigenically different.

A rare but potentially fatal cause of pancytopenia is acute hemophagocytic syndrome, a condition more commonly seen in rheumatologic pediatric patients. It is frequently a diagnosis of exclusion in adults. Pancytopenia, hypertriglyceridemia, elevated transaminase and ferritin characterize the diseases. Overwhelming inflammatory response, coagulopathy, pulmonary involvement and encephalopathy are the most common clinical manifestations. Bone marrow examination is diagnostic. Treatments include high dose steroids, IVIG and cyclosporine.

Musculoskeletal Involvement

Muscular involvement is a characteristic feature of many connective tissue diseases although do not constitute usually an indication for ICU admission except when impairment of the respiratory dynamic is present. Rheumatic inflammatory myopathies can be confused with critical illness myopathy in debilitated patient with prolonged ICU stay.

Immobilization, steroids, and neuromuscular blocking agent are usually associated with the latter. Difficult weaning from mechanical ventilation may contribute further to increase in length of stay in these patients.

Endocrine/Adrenal Insufficiency

Chronic steroids therapy used in the treatment of numerous rheumatologic conditions increase the risk of adrenal insufficiency in acutely critically ill patients. Refractory hypotension and severe electrolytes imbalance may be present.

Stress dose steroids should be initiated (200-300 mg IV daily in divided doses) during an acute illness or high metabolic state.

Vasculitides

The presence of inflammatory leukocytes in a vessel wall and the reactive damage caused to the wall structures define vasculitis. Attack by leukocytes leads to loss of vessel integrity causing bleeding, with subsequent obstruction of the blood vessel lumen ultimately leading to tissue ischemia and necrosis. What triggers this cascade of events is unclear, but it is likely multifactorial. The size and location of the affected vessel and the presence or absence of antineutrophil cytoplasmic antibodies (ANCA) form the basis of the current classification system. The affected organs, and thus the clinical presentation, depend on the presence of the target antigen in the particular organ, on the ability of the endothelial cell to respond to the antigenic presence by activating and recruiting the elements involved in initiating and sustaining the inflammatory cascade.

The American College of Rheumatology (ACR) 1990 criteria was proposed with the intent of facilitating the task of distinguishing the different types of vasculitides. The criteria do not include all the features of each particular form of vasculitis, but mainly focus on those that commonly identify the particular syndrome and to allow for comparable subjects to be included in studies and discussions. The 2012 International Chapel Hill Consensus Conference (CHCC) revised the nomenclature used to categorize the vasculitides. The accompanying tables represent a combination of both the ACR criteria and the CHCC nomenclature, as a general reference point. However, the focus of this discussion is the management of the patient with vasculitis who requires admission to the ICU. Patients with vasculitides are frequently admitted to the ICU because of complications of the immunosuppressive therapy used to control the disease, such as severe infections associated with organ dysfunction, or because of life-threatening manifestations of the disease, such as the pulmonary-renal syndrome. Most patients are admitted to the ICU with a pre-existent diagnosis of vasculitis, but in some cases their ICU admission constitutes the presentation of the disease. Unfortunately, the clinical manifestations of many of the vasculitides are nonspecific and seen in a number of conditions that present with systemic involvement, for example, multiorgan dysfunction seen in conditions such as endocarditis, severe sepsis, meningococcemia, DIC, and TTP. A high index of suspicion is therefore paramount as vasculitides, if severe and untreated, can rapidly deteriorate into life-threatening scenarios.

A potentially devastating cause for admission to the ICU for the patient with vasculitis is hemoptysis. Patients with vasculitides are frequently admitted to the ICU with manifestations of the pulmonary-renal syndrome (PRS), the combination of pulmonary hemorrhage and glomerulonephritis. Although anti-GBM disease (Goodpasture's disease) and lupus are responsible for some of the cases of PRS, the small vessel vasculitides account for most. These include the ANCA-positive vasculitides, namely eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome), GPA, and microscopic polyangiitis (MPA). Less common culprits of PRS are the ANCA-negative IgA nephropathy and Henoch–Schonlein purpura. The clinical presentation and diagnostic features of each of the syndrome are summarized in the accompanying tables.

Anti-GBM disease (formerly known as Goodpasture's disease) is an uncommon cause of PRS. It is not a vasculitis, but rather a disorder mediated by antibodies directed against the α3 chain of type IV collagen found in the glomerular basement membrane and the alveolar capillaries. The spectrum of anti-GBM disease includes patients with glomerulonephritis but without pulmonary hemorrhage, or “renal-limited anti-GBM antibody disease,” and those with both glomerulonephritis and pulmonary hemorrhage. Patients present with glomerulonephritis, hemoptysis (could be episodic or acute and massive), and constitutional symptoms such as fever, weight loss, malaise, anorexia, and arthralgia. Hemoptysis may be the only presenting complaint, in association with normal renal function. However, rapidly progressive renal failure associated with hematuria is the most common presenting manifestation of anti-GBM disease. Urinalysis shows hematuria with dysmorphic red cells and red cell casts, and proteinuria, usually non-nephrotic in range. Histologically there is crescent formation within glomeruli. CXR may be normal or may show bilateral alveolar infiltrates, mostly in the perihilar and lower lung areas, which resolve over a few days after cessation of bleeding. Diagnosis depends on the demonstration of anti-GBM antibodies in the appropriate clinical setting. About 20% to 30% of patients are also “ANCA positive,” and their disease behaves more like a vasculitis. Renal biopsy is necessary for confirmation of the disease. It shows crescentic glomerulonephritis and linear deposition of IgG along the glomerular basement membrane. Early diagnosis and treatment are crucial in order to prevent progression to ESRD and dialysis dependence. Treatment, as soon as the diagnosis is suspected, involves a combination of steroids, cyclophosphamide, and plasmapheresis. Good outcomes are usually seen in patients with less than 30% crescents on renal biopsy. Prognosis in anti-GBM correlates with the level of renal injury at the time of presentation. Patients with more than 50% crescents on renal biopsy, with serum Cr more than 7 or requiring dialysis with 72 hours of presentation, have poor outcomes. In these patients the benefits of combined therapy are questioned, and many would not recommend it. In these patients, a short course of steroids and plasma exchange is recommended.

The general evaluation of a patient with suspected vasculitis should include routine tests for evaluation of organ dysfunction, such as renal, hematologic, and, liver function tests; ESR and CRP as markers of inflammatory states; ANCA; anti-GBM antibody, for exclusion of Goodpasture's syndrome, Hep B and Hep C serologies; HIV testing; complement levels (C3, C4, CH50; decreased in SLE and cryoglobulinemia), RA (when elevated suggests RA, cryoglobulinemia-associated vasculitis, and SJ); cryoglobulins (seen in mixed essential cryoglobulinemia and in certain forms of vasculitis); CPK to rule out myositis (associated with some vasculitides). Blood cultures should routinely be performed to rule out infection. A CXR, chest CT (if abnormal CXR findings or in cases of pulmonary manifestations not explained by CXR), UA, and EKG may be warranted. If indicated, a lumbar puncture should be performed. Patients with pulmonary hemorrhage usually have pulmonary capillaritis from small vessel vasculitis secondary to GPA and MPA more often than to anti-GBM and cryoglobulinemic vasculitis; it is rare in EGPA and IgAV. Bronchoscopy is performed to rule out other causes of pulmonary hemorrhage, such as infection, malignancy, among others and to establish the presence of alveolar hemorrhage. Tissue biopsy is almost always necessary in order to confirm the presence of a vasculitis.

The management of the patient with PRS involves supportive care and the use of immunosuppressants. Airway management should follow the usual protocols used in the care of patients with respiratory failure, such as lung protective ventilation. The patient with GPA, however, may represent a special challenge due to the occasional occurrence of tracheal stenosis. Infections are a common cause of mortality among these patients, and their occurrence requires diligent surveillance, especially because of the increased risk afforded by the use of immunosuppressants.

Glucocorticoids are the mainstay of therapy in vasculitides. However, the use of cytotoxic agents in addition to steroids has improved the survival of this patient population. The challenge resides in identifying the patient in whom the benefit-risk assessment favors the additional risks of cytotoxic agents. The severity of vasculitis has not been identified as a prognostic marker, in contrast to the presence of respiratory failure, which has been associated with worse outcomes. ANCA titers are not uniformly reflective of disease severity. The revised 2011 Five Factors Score (FFS) has been used to assess the severity of vasculitis and to identify the patient whose survival can be favorably impacted by the addition of cytotoxic agents. In the FFS scoring system a point is given for the presence of each of the following:

• Cardiac involvement

• GI involvement

• Renal injury (peak serum Cr > 1.7 mg/dL)

• Age > 65

• Absence of ENT manifestations (in EGPA)

The 1996 version of the FFS system included proteinuria and CNS involvement. The score ranges from 0 (none of the factors are present) to 2 (2 or more factors are present). The greater the number of factors present, the worse the prognosis, with cardiac and GI involvement being the strongest negative prognostic indicators. The patient with a FFS of 1 has a 26% 5-year mortality risk according to some series. Based on these findings, it follows that patients with FFS of 1 or greater, patients with cardiac and/or gastrointestinal manifestations, as well as the obvious subset of patients with refractory disease, would benefit from the concomitant use of cytotoxic agents.

In general, the treatment of systemic vasculitis entails an induction phase, which typically can last up to 1 to 2 months, and a maintenance phase, which can last 1 to 2 years, or longer. The induction phase uses high dose steroids (IV methylprednisolone 1 g daily for 3 to 5 days, replaced then by prednisone 1 mg/kg/d) and, when indicated, a cytotoxic agent, such as cyclophosphamide, IV or PO. Compared to oral cyclophosphamide, pulse IV cyclophosphamide, every 2 to 4 weeks, is associated with similar rates of induction but a higher risk of relapse. The use of IV cyclophosphamide allows a lower total cumulative dose, and therefore potentially leads to a lower incidence of adverse reactions, especially infectious. Azathioprine and methotrexate have been used in less severe cases of vasculitides and in patients intolerant of cyclophosphamide. These agents are also used after the induction phase with cyclophosphamide in some cases. In patients with life-threatening pulmonary hemorrhage or rapidly progressing glomerulonephritis, plasmapheresis can be used as an adjunct to immunosuppression, although it offers no mortality benefit. The role of plasmapheresis in ANCA-negative glomerulonephritis is not supported by data. Iv IG can be considered in patients with a concurrent, serious infection, in whom cytotoxic agents carry a greater risk of adverse events. In terms of monitoring of the response to therapy, standardized risk scores, decreasing ANCA levels as in the case of GPA and microscopic polyangiitis, can be used to guide therapy aggressiveness and the transition from induction to maintenance phases of treatment. Prophylaxis against opportunistic infections, especially Pneumocystis, is indicated during the period of immunosuppression.

Mortality in patients with vasculitis admitted to the ICU ranges from 11% to 40%, mostly secondary to infections. Early deaths in patients with vasculitis are usually secondary to the disease itself, whereas late mortalities are usually attributed to infectious complications, usually as result of treatment (Table 46–3).

Overall rheumatologic critically ill patients have very high in-ICU mortality, therefore, early diagnosis and treatment should be sought in order to significantly impact mortality and morbidity. It is necessary to distinguish up front a disease flare versus an infectious process since initiation of immunosuppressive therapy may be fatal in severe septic patients. Aggressive treatment with high dose steroids, disease modifying antirheumatic-cytotoxic drugs and new biological agents must be tailored individually to achieve remission in case of active disease. Adjuvant measures such as plasma exchange and intravenous immunoglobulin are used for nonresponsive patients or for life threatening conditions. No clear prognosticator of in-ICU mortality has been identified as applicable to single patient yet, but intuitively high Apache score, multiorgan failure, comorbidities, advanced age and pancytopenia were all associated with worse outcome.