Cleveland Clinic Journal of Medicine

Bisphosphonates, especially intravenous zoledronic acid, often cause influenza-like symptoms such as severe musculoskeletal pain, fever, headache, malaise, and fatigue, sometimes accompanied by nausea, vomiting, and diarrhea. As many as 30% of patients experience these symptoms, which are usually transient, last up to 1 week, and, in most patients, only rarely recur with subsequent infusions.

It is essential to counsel and reassure patients about these reactions before starting treatment. We recommend that patients take acetaminophen before intravenous bis­phosphonate infusions, and if an acute-phase reaction occurs, we provide adequate supportive care with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). If patients report severe musculoskeletal pain, then consider discontinuing the bisphosphonate treatment.

INFLUENZA-LIKE SYMPTOMS

The acute-phase reaction is a transient inflammatory state characterized by influenza-like symptoms such as fever, myalgia, joint pain, and nausea. It often occurs within the first few days after initial exposure to a bisphosphonate. Patients tend to rate the symptoms as mild to moderate. Symptoms may recur with subsequent doses; however, the incidence rate decreases substantially with each subsequent dose.

With intravenous bisphosphonates

Reid et al1 analyzed data from a trial in which 7,765 postmenopausal women with osteoporosis were randomized to receive intravenous zoledronic acid or placebo; 42.4% of the zoledronic acid group experienced symptoms that could be attributed to an acute-phase reaction after the first infusion, compared with 11.7% of the placebo group (P < .0001). Statistically significant differences (P < .0001) in symptoms between the groups included the following:

• Fever 20.3% vs 2.5%
• Musculoskeletal symptoms 19.9% vs 4.7% 
• Gastrointestinal symptoms 7.8% vs 2.1%.

Of the patients describing musculoskeletal symptoms after receiving zoledronic acid, most (79%) described them as generalized pain or discomfort, while about 25% said they were regional, usually localized to the back, neck, chest, and shoulders, 5% described joint stiffness, and 2.5% reported joint swelling.¹

In this and other studies,^1–3 acute-phase reactions most commonly occurred within the first few days after the infusion and were rated as mild to moderate in 90% of cases.^1,2 Patients who reported an acute-phase reaction were not more likely to opt out of subsequent infusions. The authors postulated that this was most likely because acute-phase reactions were mild and transient, and most resolved within 1 week.¹ The incidence decreased with each subsequent infusion of zoledronic acid^1–3; rates of the acute-phase reaction at years 1, 2, and 3 were 30%, 7%, and 3%, respectively.¹

With oral bisphosphonates

The acute-phase reaction is less common with oral bisphosphonates (occurring in 5.6% of patients in a retrospective study4) and is usually less severe.^4,5

Musculoskeletal pain related to the acute-phase reaction is thought to be due to transient release of inflammatory cytokines such as interleukin 6, interferon gamma, and tumor necrosis factor alpha from macrophages, monocytes, and gamma-delta T cells.⁶

Bisphosphonates are taken up by osteoclasts and inhibit their function. But bisphosphonates are not all the same: they can be divided into aminobisphosphonates (eg, alendronate, pamidronate, risedronate, zoledronic acid) and nonaminobisphosphonates (eg, clodronate, etidronate).

Inside the osteoclasts, aminobisphosphonates inhibit farnesyl diphosphate synthase in the meval­onate pathways, thus disrupting cell signaling and leading to apoptosis.⁷ However, inhibition of farnesyl diphosphate synthase also increases intracellular levels of isopentyl pyrophosphate, which induces T-cell activation; this is thought to result in release of inflammatory cytokines, leading to the acute-phase reaction.^7,8

In contrast, nonaminobisphosphonates such as clodronate and etidronate, after being internalized, are metabolized into nonhydrolyzable adenosine triphosphate, which is toxic to the osteoclast. The acute-phase reaction or influenza-like illness is unique to aminobisphosphonates; nonaminobisphosphonates have not been associated with an acute-phase reaction.

TRIALS OF PREVENTIVE TREATMENT

With NSAIDs, acetaminophen

Wark et al⁹ randomized 481 postmenopausal women who had osteopenia but who had never received bisphosphonates to 4 treatment groups:

• Zoledronic acid 5 mg intravenously plus acetaminophen 1,000 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus ibuprofen 400 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus 2 placebo capsules every 6 hours for 3 days
• Placebo infusion plus 2 placebo capsules every 6 hours for 3 days.

Patients were assessed for fever and worsening symptoms over 3 days after the infusion. The group that got zoledronic acid infusion and placebo capsules had the highest rates of fever (64%) and worsening symptoms (76%); acetaminophen and ibuprofen reduced these rates to an approximately equal extent, to 37% for fever and 46% (acetaminophen) and 49% (ibuprofen) for worsening symptoms. The group that received placebo bisphosphonate infusions had the lowest rates of fever (11%) and worsening symptoms (17%).

Silverman et al¹⁰ found that acetaminophen 650 mg taken 45 minutes before intravenous zoledronic acid infusion and continued every 6 hours for 3 days led to an absolute risk reduction of 21% in the incidence of fever or use of rescue medication compared with placebo.

Trials of other agents

In a study of 60 women,¹¹ 30 received an oral bolus of cholecalciferol 300,000 IU 5 days before zoledronic acid 5 mg infusion plus daily calcium 1,000 mg and vitamin D 800 IU, and 30 received a placebo pill 5 days before the same infusion and vitamin regimen as the other group. The preinfusion oral bolus did not decrease the incidence of acute-phase reactions, although it led to a small decrease in the severity of musculoskeletal pain (the median pain score was reduced from 2 to 1 on a scale of 0 to 10).

Other interventions such as fluvastatin and oral dexamethasone given before intravenous zoledronic acid did not reduce the severity or incidence of the acute-phase reaction.^10,12,13

Before starting bisphosphonate therapy, patients should be counseled about the possibility of acute musculoskeletal pain and other symptoms of the acute-phase reaction.

For intravenous bisphosphonates

We advise all patients scheduled to receive intravenous bisphosphonates to take acetaminophen 650 to 1,000 mg once on the morning of the infusion. We prefer acetaminophen over NSAIDs for prophylaxis to avoid the gastric mucosal and renal toxicity more common with NSAIDs, especially in the elderly.

If the patient has a history of acute musculoskeletal pain or other symptoms of an acute-phase reaction after bisphosphonate infusion, we advise a more aggressive approach to prophylaxis: acetaminophen 650 mg 1 hour before the infusion, then every 6 hours for up to 3 days. This approach, with acetaminophen or NSAIDs, has been shown in large randomized controlled trials to reduce the incidence and severity of the acute-phase reaction.

If an acute-phase reaction occurs, we inform patients that the likelihood decreases and is quite low with subsequent doses. We provide correct and honest information, so that patients who experience an acute-phase reaction can make an informed decision about continuing bisphosphonate treatment or switching to another treatment. If the patient decides to continue with intravenous bisphosphonate treatment, we recommend more-aggressive prophylaxis with acetaminophen or NSAIDs with subsequent infusions.

For oral bisphosphonates

We do not prescribe prophylactic treatment with acetaminophen or NSAIDs with oral bisphosphonates, but we do advise patients to take acetaminophen or NSAIDs as needed for mild to moderate musculoskeletal pain, should this occur.

We try to continue treatment in mild to moderate cases, while monitoring the patient closely to see if the musculoskeletal pain resolves within 1 to 2 weeks.

If the pain is severe or does not resolve in 1 to 2 weeks, we offer switching to another drug class. Since musculoskeletal pain with oral bisphosphonates does not represent an allergic reaction, we have switched patients from oral to intravenous bisphosphonates without recurrence of musculoskeletal pain.

SEVERE MUSCULOSKELETAL PAIN BEYOND THE ACUTE PHASE

Severe musculoskeletal pain that may not be related to the acute-phase reaction, although rare, has been reported.^5,14 From 1995, when alendronate was approved for osteoporosis, through 2002, the US Food and Drug Administration received reports of severe musculoskeletal pain in 117 patients.¹⁵

This severe musculoskeletal pain related to bisphosphonate use remains poorly characterized. It has been reported to occur days or months (median time 14 days, range same day to 52 months) after starting bisphosphonate therapy and to resolve only if the bisphosphonate is stopped.^5,15 It differs from typical acute-phase reactions, which tend to occur with the initial dose (intravenous or oral) and resolve within several days. There are case reports of polyarthritis with synovitis that recurred with each bisphosphonate dose (oral or intravenous) and led to discontinuation of the bisphosphonate.^14,16–18

Clinicians need to be aware of the possibility of severe musculoskeletal pain and consider stopping bisphosphonate treatment in these cases. Besides discontinuation, acetaminophen, NSAIDs, and, in rare cases, glucocorticoids or short-term opiate therapy may be used for symptom control. In patients with a severe or persistent acute-phase reaction or musculoskeletal pain, discontinuation of bisphosphonates is warranted.

Bisphosphonates, especially intravenous zoledronic acid, often cause influenza-like symptoms such as severe musculoskeletal pain, fever, headache, malaise, and fatigue, sometimes accompanied by nausea, vomiting, and diarrhea. As many as 30% of patients experience these symptoms, which are usually transient, last up to 1 week, and, in most patients, only rarely recur with subsequent infusions.

It is essential to counsel and reassure patients about these reactions before starting treatment. We recommend that patients take acetaminophen before intravenous bis­phosphonate infusions, and if an acute-phase reaction occurs, we provide adequate supportive care with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). If patients report severe musculoskeletal pain, then consider discontinuing the bisphosphonate treatment.

INFLUENZA-LIKE SYMPTOMS

The acute-phase reaction is a transient inflammatory state characterized by influenza-like symptoms such as fever, myalgia, joint pain, and nausea. It often occurs within the first few days after initial exposure to a bisphosphonate. Patients tend to rate the symptoms as mild to moderate. Symptoms may recur with subsequent doses; however, the incidence rate decreases substantially with each subsequent dose.

With intravenous bisphosphonates

Reid et al1 analyzed data from a trial in which 7,765 postmenopausal women with osteoporosis were randomized to receive intravenous zoledronic acid or placebo; 42.4% of the zoledronic acid group experienced symptoms that could be attributed to an acute-phase reaction after the first infusion, compared with 11.7% of the placebo group (P < .0001). Statistically significant differences (P < .0001) in symptoms between the groups included the following:

• Fever 20.3% vs 2.5%
• Musculoskeletal symptoms 19.9% vs 4.7% 
• Gastrointestinal symptoms 7.8% vs 2.1%.

Of the patients describing musculoskeletal symptoms after receiving zoledronic acid, most (79%) described them as generalized pain or discomfort, while about 25% said they were regional, usually localized to the back, neck, chest, and shoulders, 5% described joint stiffness, and 2.5% reported joint swelling.¹

In this and other studies,^1–3 acute-phase reactions most commonly occurred within the first few days after the infusion and were rated as mild to moderate in 90% of cases.^1,2 Patients who reported an acute-phase reaction were not more likely to opt out of subsequent infusions. The authors postulated that this was most likely because acute-phase reactions were mild and transient, and most resolved within 1 week.¹ The incidence decreased with each subsequent infusion of zoledronic acid^1–3; rates of the acute-phase reaction at years 1, 2, and 3 were 30%, 7%, and 3%, respectively.¹

With oral bisphosphonates

The acute-phase reaction is less common with oral bisphosphonates (occurring in 5.6% of patients in a retrospective study4) and is usually less severe.^4,5

Musculoskeletal pain related to the acute-phase reaction is thought to be due to transient release of inflammatory cytokines such as interleukin 6, interferon gamma, and tumor necrosis factor alpha from macrophages, monocytes, and gamma-delta T cells.⁶

Bisphosphonates are taken up by osteoclasts and inhibit their function. But bisphosphonates are not all the same: they can be divided into aminobisphosphonates (eg, alendronate, pamidronate, risedronate, zoledronic acid) and nonaminobisphosphonates (eg, clodronate, etidronate).

Inside the osteoclasts, aminobisphosphonates inhibit farnesyl diphosphate synthase in the meval­onate pathways, thus disrupting cell signaling and leading to apoptosis.⁷ However, inhibition of farnesyl diphosphate synthase also increases intracellular levels of isopentyl pyrophosphate, which induces T-cell activation; this is thought to result in release of inflammatory cytokines, leading to the acute-phase reaction.^7,8

In contrast, nonaminobisphosphonates such as clodronate and etidronate, after being internalized, are metabolized into nonhydrolyzable adenosine triphosphate, which is toxic to the osteoclast. The acute-phase reaction or influenza-like illness is unique to aminobisphosphonates; nonaminobisphosphonates have not been associated with an acute-phase reaction.

TRIALS OF PREVENTIVE TREATMENT

With NSAIDs, acetaminophen

Wark et al⁹ randomized 481 postmenopausal women who had osteopenia but who had never received bisphosphonates to 4 treatment groups:

• Zoledronic acid 5 mg intravenously plus acetaminophen 1,000 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus ibuprofen 400 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus 2 placebo capsules every 6 hours for 3 days
• Placebo infusion plus 2 placebo capsules every 6 hours for 3 days.

Patients were assessed for fever and worsening symptoms over 3 days after the infusion. The group that got zoledronic acid infusion and placebo capsules had the highest rates of fever (64%) and worsening symptoms (76%); acetaminophen and ibuprofen reduced these rates to an approximately equal extent, to 37% for fever and 46% (acetaminophen) and 49% (ibuprofen) for worsening symptoms. The group that received placebo bisphosphonate infusions had the lowest rates of fever (11%) and worsening symptoms (17%).

Silverman et al¹⁰ found that acetaminophen 650 mg taken 45 minutes before intravenous zoledronic acid infusion and continued every 6 hours for 3 days led to an absolute risk reduction of 21% in the incidence of fever or use of rescue medication compared with placebo.

Trials of other agents

In a study of 60 women,¹¹ 30 received an oral bolus of cholecalciferol 300,000 IU 5 days before zoledronic acid 5 mg infusion plus daily calcium 1,000 mg and vitamin D 800 IU, and 30 received a placebo pill 5 days before the same infusion and vitamin regimen as the other group. The preinfusion oral bolus did not decrease the incidence of acute-phase reactions, although it led to a small decrease in the severity of musculoskeletal pain (the median pain score was reduced from 2 to 1 on a scale of 0 to 10).

Other interventions such as fluvastatin and oral dexamethasone given before intravenous zoledronic acid did not reduce the severity or incidence of the acute-phase reaction.^10,12,13

Before starting bisphosphonate therapy, patients should be counseled about the possibility of acute musculoskeletal pain and other symptoms of the acute-phase reaction.

For intravenous bisphosphonates

We advise all patients scheduled to receive intravenous bisphosphonates to take acetaminophen 650 to 1,000 mg once on the morning of the infusion. We prefer acetaminophen over NSAIDs for prophylaxis to avoid the gastric mucosal and renal toxicity more common with NSAIDs, especially in the elderly.

If the patient has a history of acute musculoskeletal pain or other symptoms of an acute-phase reaction after bisphosphonate infusion, we advise a more aggressive approach to prophylaxis: acetaminophen 650 mg 1 hour before the infusion, then every 6 hours for up to 3 days. This approach, with acetaminophen or NSAIDs, has been shown in large randomized controlled trials to reduce the incidence and severity of the acute-phase reaction.

If an acute-phase reaction occurs, we inform patients that the likelihood decreases and is quite low with subsequent doses. We provide correct and honest information, so that patients who experience an acute-phase reaction can make an informed decision about continuing bisphosphonate treatment or switching to another treatment. If the patient decides to continue with intravenous bisphosphonate treatment, we recommend more-aggressive prophylaxis with acetaminophen or NSAIDs with subsequent infusions.

For oral bisphosphonates

We do not prescribe prophylactic treatment with acetaminophen or NSAIDs with oral bisphosphonates, but we do advise patients to take acetaminophen or NSAIDs as needed for mild to moderate musculoskeletal pain, should this occur.

We try to continue treatment in mild to moderate cases, while monitoring the patient closely to see if the musculoskeletal pain resolves within 1 to 2 weeks.

If the pain is severe or does not resolve in 1 to 2 weeks, we offer switching to another drug class. Since musculoskeletal pain with oral bisphosphonates does not represent an allergic reaction, we have switched patients from oral to intravenous bisphosphonates without recurrence of musculoskeletal pain.

SEVERE MUSCULOSKELETAL PAIN BEYOND THE ACUTE PHASE

Severe musculoskeletal pain that may not be related to the acute-phase reaction, although rare, has been reported.^5,14 From 1995, when alendronate was approved for osteoporosis, through 2002, the US Food and Drug Administration received reports of severe musculoskeletal pain in 117 patients.¹⁵

This severe musculoskeletal pain related to bisphosphonate use remains poorly characterized. It has been reported to occur days or months (median time 14 days, range same day to 52 months) after starting bisphosphonate therapy and to resolve only if the bisphosphonate is stopped.^5,15 It differs from typical acute-phase reactions, which tend to occur with the initial dose (intravenous or oral) and resolve within several days. There are case reports of polyarthritis with synovitis that recurred with each bisphosphonate dose (oral or intravenous) and led to discontinuation of the bisphosphonate.^14,16–18

Clinicians need to be aware of the possibility of severe musculoskeletal pain and consider stopping bisphosphonate treatment in these cases. Besides discontinuation, acetaminophen, NSAIDs, and, in rare cases, glucocorticoids or short-term opiate therapy may be used for symptom control. In patients with a severe or persistent acute-phase reaction or musculoskeletal pain, discontinuation of bisphosphonates is warranted.

Bisphosphonates, especially intravenous zoledronic acid, often cause influenza-like symptoms such as severe musculoskeletal pain, fever, headache, malaise, and fatigue, sometimes accompanied by nausea, vomiting, and diarrhea. As many as 30% of patients experience these symptoms, which are usually transient, last up to 1 week, and, in most patients, only rarely recur with subsequent infusions.

It is essential to counsel and reassure patients about these reactions before starting treatment. We recommend that patients take acetaminophen before intravenous bis­phosphonate infusions, and if an acute-phase reaction occurs, we provide adequate supportive care with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). If patients report severe musculoskeletal pain, then consider discontinuing the bisphosphonate treatment.

INFLUENZA-LIKE SYMPTOMS

The acute-phase reaction is a transient inflammatory state characterized by influenza-like symptoms such as fever, myalgia, joint pain, and nausea. It often occurs within the first few days after initial exposure to a bisphosphonate. Patients tend to rate the symptoms as mild to moderate. Symptoms may recur with subsequent doses; however, the incidence rate decreases substantially with each subsequent dose.

With intravenous bisphosphonates

Reid et al1 analyzed data from a trial in which 7,765 postmenopausal women with osteoporosis were randomized to receive intravenous zoledronic acid or placebo; 42.4% of the zoledronic acid group experienced symptoms that could be attributed to an acute-phase reaction after the first infusion, compared with 11.7% of the placebo group (P < .0001). Statistically significant differences (P < .0001) in symptoms between the groups included the following:

• Fever 20.3% vs 2.5%
• Musculoskeletal symptoms 19.9% vs 4.7% 
• Gastrointestinal symptoms 7.8% vs 2.1%.

Of the patients describing musculoskeletal symptoms after receiving zoledronic acid, most (79%) described them as generalized pain or discomfort, while about 25% said they were regional, usually localized to the back, neck, chest, and shoulders, 5% described joint stiffness, and 2.5% reported joint swelling.¹

In this and other studies,^1–3 acute-phase reactions most commonly occurred within the first few days after the infusion and were rated as mild to moderate in 90% of cases.^1,2 Patients who reported an acute-phase reaction were not more likely to opt out of subsequent infusions. The authors postulated that this was most likely because acute-phase reactions were mild and transient, and most resolved within 1 week.¹ The incidence decreased with each subsequent infusion of zoledronic acid^1–3; rates of the acute-phase reaction at years 1, 2, and 3 were 30%, 7%, and 3%, respectively.¹

With oral bisphosphonates

The acute-phase reaction is less common with oral bisphosphonates (occurring in 5.6% of patients in a retrospective study4) and is usually less severe.^4,5

Musculoskeletal pain related to the acute-phase reaction is thought to be due to transient release of inflammatory cytokines such as interleukin 6, interferon gamma, and tumor necrosis factor alpha from macrophages, monocytes, and gamma-delta T cells.⁶

Bisphosphonates are taken up by osteoclasts and inhibit their function. But bisphosphonates are not all the same: they can be divided into aminobisphosphonates (eg, alendronate, pamidronate, risedronate, zoledronic acid) and nonaminobisphosphonates (eg, clodronate, etidronate).

Inside the osteoclasts, aminobisphosphonates inhibit farnesyl diphosphate synthase in the meval­onate pathways, thus disrupting cell signaling and leading to apoptosis.⁷ However, inhibition of farnesyl diphosphate synthase also increases intracellular levels of isopentyl pyrophosphate, which induces T-cell activation; this is thought to result in release of inflammatory cytokines, leading to the acute-phase reaction.^7,8

In contrast, nonaminobisphosphonates such as clodronate and etidronate, after being internalized, are metabolized into nonhydrolyzable adenosine triphosphate, which is toxic to the osteoclast. The acute-phase reaction or influenza-like illness is unique to aminobisphosphonates; nonaminobisphosphonates have not been associated with an acute-phase reaction.

TRIALS OF PREVENTIVE TREATMENT

With NSAIDs, acetaminophen

Wark et al⁹ randomized 481 postmenopausal women who had osteopenia but who had never received bisphosphonates to 4 treatment groups:

• Zoledronic acid 5 mg intravenously plus acetaminophen 1,000 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus ibuprofen 400 mg every 6 hours for 3 days
• Zoledronic acid 5 mg intravenously plus 2 placebo capsules every 6 hours for 3 days
• Placebo infusion plus 2 placebo capsules every 6 hours for 3 days.

Patients were assessed for fever and worsening symptoms over 3 days after the infusion. The group that got zoledronic acid infusion and placebo capsules had the highest rates of fever (64%) and worsening symptoms (76%); acetaminophen and ibuprofen reduced these rates to an approximately equal extent, to 37% for fever and 46% (acetaminophen) and 49% (ibuprofen) for worsening symptoms. The group that received placebo bisphosphonate infusions had the lowest rates of fever (11%) and worsening symptoms (17%).

Silverman et al¹⁰ found that acetaminophen 650 mg taken 45 minutes before intravenous zoledronic acid infusion and continued every 6 hours for 3 days led to an absolute risk reduction of 21% in the incidence of fever or use of rescue medication compared with placebo.

Trials of other agents

In a study of 60 women,¹¹ 30 received an oral bolus of cholecalciferol 300,000 IU 5 days before zoledronic acid 5 mg infusion plus daily calcium 1,000 mg and vitamin D 800 IU, and 30 received a placebo pill 5 days before the same infusion and vitamin regimen as the other group. The preinfusion oral bolus did not decrease the incidence of acute-phase reactions, although it led to a small decrease in the severity of musculoskeletal pain (the median pain score was reduced from 2 to 1 on a scale of 0 to 10).

Other interventions such as fluvastatin and oral dexamethasone given before intravenous zoledronic acid did not reduce the severity or incidence of the acute-phase reaction.^10,12,13

Before starting bisphosphonate therapy, patients should be counseled about the possibility of acute musculoskeletal pain and other symptoms of the acute-phase reaction.

For intravenous bisphosphonates

We advise all patients scheduled to receive intravenous bisphosphonates to take acetaminophen 650 to 1,000 mg once on the morning of the infusion. We prefer acetaminophen over NSAIDs for prophylaxis to avoid the gastric mucosal and renal toxicity more common with NSAIDs, especially in the elderly.

If the patient has a history of acute musculoskeletal pain or other symptoms of an acute-phase reaction after bisphosphonate infusion, we advise a more aggressive approach to prophylaxis: acetaminophen 650 mg 1 hour before the infusion, then every 6 hours for up to 3 days. This approach, with acetaminophen or NSAIDs, has been shown in large randomized controlled trials to reduce the incidence and severity of the acute-phase reaction.

If an acute-phase reaction occurs, we inform patients that the likelihood decreases and is quite low with subsequent doses. We provide correct and honest information, so that patients who experience an acute-phase reaction can make an informed decision about continuing bisphosphonate treatment or switching to another treatment. If the patient decides to continue with intravenous bisphosphonate treatment, we recommend more-aggressive prophylaxis with acetaminophen or NSAIDs with subsequent infusions.

For oral bisphosphonates

We do not prescribe prophylactic treatment with acetaminophen or NSAIDs with oral bisphosphonates, but we do advise patients to take acetaminophen or NSAIDs as needed for mild to moderate musculoskeletal pain, should this occur.

We try to continue treatment in mild to moderate cases, while monitoring the patient closely to see if the musculoskeletal pain resolves within 1 to 2 weeks.

If the pain is severe or does not resolve in 1 to 2 weeks, we offer switching to another drug class. Since musculoskeletal pain with oral bisphosphonates does not represent an allergic reaction, we have switched patients from oral to intravenous bisphosphonates without recurrence of musculoskeletal pain.

SEVERE MUSCULOSKELETAL PAIN BEYOND THE ACUTE PHASE

Severe musculoskeletal pain that may not be related to the acute-phase reaction, although rare, has been reported.^5,14 From 1995, when alendronate was approved for osteoporosis, through 2002, the US Food and Drug Administration received reports of severe musculoskeletal pain in 117 patients.¹⁵

This severe musculoskeletal pain related to bisphosphonate use remains poorly characterized. It has been reported to occur days or months (median time 14 days, range same day to 52 months) after starting bisphosphonate therapy and to resolve only if the bisphosphonate is stopped.^5,15 It differs from typical acute-phase reactions, which tend to occur with the initial dose (intravenous or oral) and resolve within several days. There are case reports of polyarthritis with synovitis that recurred with each bisphosphonate dose (oral or intravenous) and led to discontinuation of the bisphosphonate.^14,16–18

Clinicians need to be aware of the possibility of severe musculoskeletal pain and consider stopping bisphosphonate treatment in these cases. Besides discontinuation, acetaminophen, NSAIDs, and, in rare cases, glucocorticoids or short-term opiate therapy may be used for symptom control. In patients with a severe or persistent acute-phase reaction or musculoskeletal pain, discontinuation of bisphosphonates is warranted.

If a patient experiences diarrhea, hematochezia, or abdominal pain within the first 6 weeks of therapy with one of the anticancer drugs known as immune checkpoint inhibitors (ICIs), the first step is to rule out infection, especially with Clostridium difficile. The next step is colonosocopy with biopsy or computed tomography.

Patients with mild ICI-associated colitis may need only supportive care, and the ICI can be continued. In moderate or severe cases, the agent may need to be stopped and corticosteroids and other colitis-targeted agents may be needed. Figure 1 shows our algorithm for diagnosing and treating ICI-associated colitis.

POWERFUL ANTICANCER DRUGS

ICIs are monoclonal antibodies used in treating metastatic melanoma, non-small-cell lung cancer, metastatic prostate cancer, Hodgkin lymphoma, renal cell carcinoma, and other advanced malignancies.^1,2 They act by binding to and blocking proteins on T cells, antigen-presenting cells, and tumor cells that keep immune responses in check and prevent T cells from killing cancer cells.¹ For example:

• Ipilimumab blocks cytotoxic T lymphocyte-associated antigen 4
• Nivolumab and pembrolizumab block programmed cell death protein 1
• Atezolizumab blocks programmed death ligand 1.¹

With these proteins blocked, T cells can do their job, often producing dramatic regression of cancer. However, ICIs can cause a range of immune-related adverse effects, including endocrine and cutaneous toxicities, iridocyclitis, lymphadenopathy, neuropathy, nephritis, immune-mediated pneumonitis, pancreatitis, hepatitis, and colitis.³

ICI-ASSOCIATED COLITIS IS COMMON

ICI-associated colitis is common; it is estimated to affect about 30% of patients receiving ipilimumab, for example.⁴ Clinical presentations range from watery bowel movements, blood or mucus in the stool, abdominal cramping, and flatulence to ileus, colectasia, intestinal perforation, and even death.⁵

The incidence appears to increase with the dosage and duration of ICI therapy. The onset of colitis typically occurs 6 to 7 weeks after starting ipilimumab,⁶ and 6 to 18 weeks after starting nivolumab or pembrolizumab.⁷Table 1 lists the incidence of diarrhea and colitis and time of onset to colitis with common ICIs. However, colitis, like other immune-related adverse events, can occur at any point, even after ICI therapy has been discontinued.⁸

It is best to detect side effects of ICIs promptly, as acute inflammation can progress to chronic inflammation within 1 month of onset.⁹ We believe that early intervention and close monitoring may prevent complications and the need for long-term immunosuppressive treatment.

Patients, family members, and caregivers should be informed of possible gastrointestinal along with systemic side effects. Severe gastrointestinal symptoms such as increased stool frequency and change in stool consistency should trigger appropriate investigation and the withholding of ICI therapy.

COLITIS IS A SPECTRUM

The colon appears to be the gastrointestinal organ most affected by ICIs. Of patients with intestinal side effects, including diarrhea, only some develop colitis. The severity of ICI-associated colitis ranges from mild bowel illness to fulminant colitis.

Hodi et al,¹⁰ in a randomized trial in which 511 patients with melanoma received ipilimumab, reported that approximately 30% had mild diarrhea, while fewer than 10% had severe diarrhea, fever, ileus, or peritoneal signs. Five patients (1%) developed intestinal perforation, 4 (0.8%) died of complications, and 26 (5%) required hospitalization for severe enterocolitis.

The pathophysiology of ICI-mediated colitis is unclear. Most cases are diagnosed clinically.

Colitis is graded based on the Montreal classification system¹¹:

Mild colitis is defined as passage of fewer than 4 stools per day (with or without blood) over baseline and absence of any systemic illness.

Moderate is passage of more than 4 stools per day but with minimal signs of systemic toxicity.

Severe is defined as passage of at least 6 stools per day, heart rate at least 90 beats per minute, temperature at least 37.5°C (99.5°F), hemoglobin less than 10.5 g/dL, and erythrocyte sedimentation rate at least 30 mm/h.¹¹

RULE OUT INFECTION

If symptoms such as diarrhea or abdominal pain arise within 6 weeks of starting ICI therapy, then we should check for an infectious cause. The differential diagnosis of suspected ICI-associated colitis includes infections with C difficile, cytomegalovirus, opportunistic organisms, and other bacteria and viruses. ICI-induced celiac disease and immune hyper­thyroidism should also be ruled out.⁴

Once infection is ruled out, colonoscopy should be considered if symptoms persist or are severe. Colonoscopy with biopsy remains the gold standard for diagnosis, and it is also helpful in assessing severity of mucosal inflammation and monitoring response to medical treatment.

Table 2 lists common endoscopic and histologic features of ICI-mediated colitis; however, none of them is specific for this disease.

Common endoscopic features are loss of vascular pattern, edema, friability, spontaneous bleeding, and deep ulcerations.¹² A recent study suggested that colonic ulcerations predict a steroid-refractory course in patients with immune-mediated colitis.⁴

Histologically, ICI-associated colitis is characterized by both acute and chronic changes, including an increased number of neutrophils and lymphocytes in the epithelium and lamina propria, erosions, ulcers, crypt abscess, crypt apoptosis, crypt distortion, and even noncaseating granulomas.¹³ However, transmural disease is rare. Figure 2 compares the histopathologic features of ICI-associated colitis and a normal colon.

COMPUTED TOMOGRAPHY CAN BE USEFUL

Computed tomography (CT) can also be useful for the diagnosis and measurement of severity.

Garcia-Neuer et al1⁴ analyzed 303 patients with advanced melanoma who developed gastrointestinal symptoms while being treated with ipilimumab. Ninety-nine (33%) of them reported diarrhea during therapy, of whom 34 underwent both CT and colonoscopy with biopsy. CT was highly predictive of colitis on biopsy, with a positive predictive value of 96% and a negative likelihood ratio of 0.2.¹⁴

TREATMENT

Supportive care may be enough when treating mild ICI-related colitis. This can include oral and intravenous hydration⁴ and an antidiarrheal drug such as loperamide in a low dose.

Corticosteroids. For moderate ICI-associated colitis with stool frequency of 4 or more per day, patients should be started on an oral corticosteroid such as prednisone 0.5 to 1 mg/kg per day. If symptoms do not improve within 72 hours of starting an oral corticosteroid, the patient should be admitted to the hospital for observation and escalation to higher doses or possibly intravenous corticosteroids.

Infliximab has been used in severe and steroid-refractory cases,¹³ although there has been concern about using anti-tumor necrosis factor (TNF) agents such as this in patients with malignancies, especially melanoma. Since melanoma can be very aggressive and anti-TNF agents may promote it, it is prudent to try not to use this class of agents.

Other biologic agents such as vedolizu­mab, a gut-specific anti-integrin agent, are safer, have theoretic advantages over anti-TNF agents, and can be considered in patients with steroid-dependent or steroid-refractory ICI-associated enterocolitis. A recent study suggested that 2 to 4 infusions of vedolizumab are adequate to achieve steroid-free remission.¹⁵ Results from 6 clinical trials of vedolizumab in 2,830 patients with Crohn disease or ulcerative colitis did not show any increased risk of serious infections or malignancies over placebo.^16,17 A drawback is its slow onset of action.

Surgery is an option for patients with severe colitis refractory to intravenous corticosteroids or biological agents, as severe colitis carries a risk of significant morbidity and even death. The incidence of bowel perforation leading to colectomy or death in patients receiving ICI therapy is 0.5% to 1%.^18,19

Fecal microbiota transplant was associated with mucosal healing after 1 month in a case report of ICI-associated colitis.⁹

Follow-up. In most patients, symptoms resolve with discontinuation of the ICI and brief use of corticosteroids or biological agents. Patients with recurrent or persistent symptoms while on long-term ICI therapy may need periodic endoscopic evaluation, especially if there are chronic structural changes on histologic study.

If patients have recurrent or persistent symptoms along with chronic inflammatory structural changes on histology, a sign of an inflammatory bowel diseaselike condition, long-term maintenance therapy with an anti-inflammatory or immunosuppressant agent may be considered. However, there is no consensus on the treatment of this condition. It can be treated in the same way as classic inflammatory bowel disease in the setting of concurrent or prior history of malignancy, especially melanoma. Certain agents used in inflammatory bowel disease such as methotrexate and vedolizumab carry a lower risk of malignancy than anti-TNF agents and can be considered. A multidisciplinary approach that includes an oncologist, gastroenterologist, infectious disease specialist, and colorectal surgeon is imperative.

If a patient experiences diarrhea, hematochezia, or abdominal pain within the first 6 weeks of therapy with one of the anticancer drugs known as immune checkpoint inhibitors (ICIs), the first step is to rule out infection, especially with Clostridium difficile. The next step is colonosocopy with biopsy or computed tomography.

Patients with mild ICI-associated colitis may need only supportive care, and the ICI can be continued. In moderate or severe cases, the agent may need to be stopped and corticosteroids and other colitis-targeted agents may be needed. Figure 1 shows our algorithm for diagnosing and treating ICI-associated colitis.

POWERFUL ANTICANCER DRUGS

ICIs are monoclonal antibodies used in treating metastatic melanoma, non-small-cell lung cancer, metastatic prostate cancer, Hodgkin lymphoma, renal cell carcinoma, and other advanced malignancies.^1,2 They act by binding to and blocking proteins on T cells, antigen-presenting cells, and tumor cells that keep immune responses in check and prevent T cells from killing cancer cells.¹ For example:

• Ipilimumab blocks cytotoxic T lymphocyte-associated antigen 4
• Nivolumab and pembrolizumab block programmed cell death protein 1
• Atezolizumab blocks programmed death ligand 1.¹

With these proteins blocked, T cells can do their job, often producing dramatic regression of cancer. However, ICIs can cause a range of immune-related adverse effects, including endocrine and cutaneous toxicities, iridocyclitis, lymphadenopathy, neuropathy, nephritis, immune-mediated pneumonitis, pancreatitis, hepatitis, and colitis.³

ICI-ASSOCIATED COLITIS IS COMMON

ICI-associated colitis is common; it is estimated to affect about 30% of patients receiving ipilimumab, for example.⁴ Clinical presentations range from watery bowel movements, blood or mucus in the stool, abdominal cramping, and flatulence to ileus, colectasia, intestinal perforation, and even death.⁵

The incidence appears to increase with the dosage and duration of ICI therapy. The onset of colitis typically occurs 6 to 7 weeks after starting ipilimumab,⁶ and 6 to 18 weeks after starting nivolumab or pembrolizumab.⁷Table 1 lists the incidence of diarrhea and colitis and time of onset to colitis with common ICIs. However, colitis, like other immune-related adverse events, can occur at any point, even after ICI therapy has been discontinued.⁸

It is best to detect side effects of ICIs promptly, as acute inflammation can progress to chronic inflammation within 1 month of onset.⁹ We believe that early intervention and close monitoring may prevent complications and the need for long-term immunosuppressive treatment.

Patients, family members, and caregivers should be informed of possible gastrointestinal along with systemic side effects. Severe gastrointestinal symptoms such as increased stool frequency and change in stool consistency should trigger appropriate investigation and the withholding of ICI therapy.

COLITIS IS A SPECTRUM

The colon appears to be the gastrointestinal organ most affected by ICIs. Of patients with intestinal side effects, including diarrhea, only some develop colitis. The severity of ICI-associated colitis ranges from mild bowel illness to fulminant colitis.

Hodi et al,¹⁰ in a randomized trial in which 511 patients with melanoma received ipilimumab, reported that approximately 30% had mild diarrhea, while fewer than 10% had severe diarrhea, fever, ileus, or peritoneal signs. Five patients (1%) developed intestinal perforation, 4 (0.8%) died of complications, and 26 (5%) required hospitalization for severe enterocolitis.

The pathophysiology of ICI-mediated colitis is unclear. Most cases are diagnosed clinically.

Colitis is graded based on the Montreal classification system¹¹:

Mild colitis is defined as passage of fewer than 4 stools per day (with or without blood) over baseline and absence of any systemic illness.

Moderate is passage of more than 4 stools per day but with minimal signs of systemic toxicity.

Severe is defined as passage of at least 6 stools per day, heart rate at least 90 beats per minute, temperature at least 37.5°C (99.5°F), hemoglobin less than 10.5 g/dL, and erythrocyte sedimentation rate at least 30 mm/h.¹¹

RULE OUT INFECTION

If symptoms such as diarrhea or abdominal pain arise within 6 weeks of starting ICI therapy, then we should check for an infectious cause. The differential diagnosis of suspected ICI-associated colitis includes infections with C difficile, cytomegalovirus, opportunistic organisms, and other bacteria and viruses. ICI-induced celiac disease and immune hyper­thyroidism should also be ruled out.⁴

Once infection is ruled out, colonoscopy should be considered if symptoms persist or are severe. Colonoscopy with biopsy remains the gold standard for diagnosis, and it is also helpful in assessing severity of mucosal inflammation and monitoring response to medical treatment.

Table 2 lists common endoscopic and histologic features of ICI-mediated colitis; however, none of them is specific for this disease.

Common endoscopic features are loss of vascular pattern, edema, friability, spontaneous bleeding, and deep ulcerations.¹² A recent study suggested that colonic ulcerations predict a steroid-refractory course in patients with immune-mediated colitis.⁴

Histologically, ICI-associated colitis is characterized by both acute and chronic changes, including an increased number of neutrophils and lymphocytes in the epithelium and lamina propria, erosions, ulcers, crypt abscess, crypt apoptosis, crypt distortion, and even noncaseating granulomas.¹³ However, transmural disease is rare. Figure 2 compares the histopathologic features of ICI-associated colitis and a normal colon.

COMPUTED TOMOGRAPHY CAN BE USEFUL

Computed tomography (CT) can also be useful for the diagnosis and measurement of severity.

Garcia-Neuer et al1⁴ analyzed 303 patients with advanced melanoma who developed gastrointestinal symptoms while being treated with ipilimumab. Ninety-nine (33%) of them reported diarrhea during therapy, of whom 34 underwent both CT and colonoscopy with biopsy. CT was highly predictive of colitis on biopsy, with a positive predictive value of 96% and a negative likelihood ratio of 0.2.¹⁴

TREATMENT

Supportive care may be enough when treating mild ICI-related colitis. This can include oral and intravenous hydration⁴ and an antidiarrheal drug such as loperamide in a low dose.

Corticosteroids. For moderate ICI-associated colitis with stool frequency of 4 or more per day, patients should be started on an oral corticosteroid such as prednisone 0.5 to 1 mg/kg per day. If symptoms do not improve within 72 hours of starting an oral corticosteroid, the patient should be admitted to the hospital for observation and escalation to higher doses or possibly intravenous corticosteroids.

Infliximab has been used in severe and steroid-refractory cases,¹³ although there has been concern about using anti-tumor necrosis factor (TNF) agents such as this in patients with malignancies, especially melanoma. Since melanoma can be very aggressive and anti-TNF agents may promote it, it is prudent to try not to use this class of agents.

Other biologic agents such as vedolizu­mab, a gut-specific anti-integrin agent, are safer, have theoretic advantages over anti-TNF agents, and can be considered in patients with steroid-dependent or steroid-refractory ICI-associated enterocolitis. A recent study suggested that 2 to 4 infusions of vedolizumab are adequate to achieve steroid-free remission.¹⁵ Results from 6 clinical trials of vedolizumab in 2,830 patients with Crohn disease or ulcerative colitis did not show any increased risk of serious infections or malignancies over placebo.^16,17 A drawback is its slow onset of action.

Surgery is an option for patients with severe colitis refractory to intravenous corticosteroids or biological agents, as severe colitis carries a risk of significant morbidity and even death. The incidence of bowel perforation leading to colectomy or death in patients receiving ICI therapy is 0.5% to 1%.^18,19

Fecal microbiota transplant was associated with mucosal healing after 1 month in a case report of ICI-associated colitis.⁹

Follow-up. In most patients, symptoms resolve with discontinuation of the ICI and brief use of corticosteroids or biological agents. Patients with recurrent or persistent symptoms while on long-term ICI therapy may need periodic endoscopic evaluation, especially if there are chronic structural changes on histologic study.

If patients have recurrent or persistent symptoms along with chronic inflammatory structural changes on histology, a sign of an inflammatory bowel diseaselike condition, long-term maintenance therapy with an anti-inflammatory or immunosuppressant agent may be considered. However, there is no consensus on the treatment of this condition. It can be treated in the same way as classic inflammatory bowel disease in the setting of concurrent or prior history of malignancy, especially melanoma. Certain agents used in inflammatory bowel disease such as methotrexate and vedolizumab carry a lower risk of malignancy than anti-TNF agents and can be considered. A multidisciplinary approach that includes an oncologist, gastroenterologist, infectious disease specialist, and colorectal surgeon is imperative.

If a patient experiences diarrhea, hematochezia, or abdominal pain within the first 6 weeks of therapy with one of the anticancer drugs known as immune checkpoint inhibitors (ICIs), the first step is to rule out infection, especially with Clostridium difficile. The next step is colonosocopy with biopsy or computed tomography.

Patients with mild ICI-associated colitis may need only supportive care, and the ICI can be continued. In moderate or severe cases, the agent may need to be stopped and corticosteroids and other colitis-targeted agents may be needed. Figure 1 shows our algorithm for diagnosing and treating ICI-associated colitis.

POWERFUL ANTICANCER DRUGS

ICIs are monoclonal antibodies used in treating metastatic melanoma, non-small-cell lung cancer, metastatic prostate cancer, Hodgkin lymphoma, renal cell carcinoma, and other advanced malignancies.^1,2 They act by binding to and blocking proteins on T cells, antigen-presenting cells, and tumor cells that keep immune responses in check and prevent T cells from killing cancer cells.¹ For example:

• Ipilimumab blocks cytotoxic T lymphocyte-associated antigen 4
• Nivolumab and pembrolizumab block programmed cell death protein 1
• Atezolizumab blocks programmed death ligand 1.¹

With these proteins blocked, T cells can do their job, often producing dramatic regression of cancer. However, ICIs can cause a range of immune-related adverse effects, including endocrine and cutaneous toxicities, iridocyclitis, lymphadenopathy, neuropathy, nephritis, immune-mediated pneumonitis, pancreatitis, hepatitis, and colitis.³

ICI-ASSOCIATED COLITIS IS COMMON

ICI-associated colitis is common; it is estimated to affect about 30% of patients receiving ipilimumab, for example.⁴ Clinical presentations range from watery bowel movements, blood or mucus in the stool, abdominal cramping, and flatulence to ileus, colectasia, intestinal perforation, and even death.⁵

The incidence appears to increase with the dosage and duration of ICI therapy. The onset of colitis typically occurs 6 to 7 weeks after starting ipilimumab,⁶ and 6 to 18 weeks after starting nivolumab or pembrolizumab.⁷Table 1 lists the incidence of diarrhea and colitis and time of onset to colitis with common ICIs. However, colitis, like other immune-related adverse events, can occur at any point, even after ICI therapy has been discontinued.⁸

It is best to detect side effects of ICIs promptly, as acute inflammation can progress to chronic inflammation within 1 month of onset.⁹ We believe that early intervention and close monitoring may prevent complications and the need for long-term immunosuppressive treatment.

Patients, family members, and caregivers should be informed of possible gastrointestinal along with systemic side effects. Severe gastrointestinal symptoms such as increased stool frequency and change in stool consistency should trigger appropriate investigation and the withholding of ICI therapy.

COLITIS IS A SPECTRUM

The colon appears to be the gastrointestinal organ most affected by ICIs. Of patients with intestinal side effects, including diarrhea, only some develop colitis. The severity of ICI-associated colitis ranges from mild bowel illness to fulminant colitis.

Hodi et al,¹⁰ in a randomized trial in which 511 patients with melanoma received ipilimumab, reported that approximately 30% had mild diarrhea, while fewer than 10% had severe diarrhea, fever, ileus, or peritoneal signs. Five patients (1%) developed intestinal perforation, 4 (0.8%) died of complications, and 26 (5%) required hospitalization for severe enterocolitis.

The pathophysiology of ICI-mediated colitis is unclear. Most cases are diagnosed clinically.

Colitis is graded based on the Montreal classification system¹¹:

Mild colitis is defined as passage of fewer than 4 stools per day (with or without blood) over baseline and absence of any systemic illness.

Moderate is passage of more than 4 stools per day but with minimal signs of systemic toxicity.

Severe is defined as passage of at least 6 stools per day, heart rate at least 90 beats per minute, temperature at least 37.5°C (99.5°F), hemoglobin less than 10.5 g/dL, and erythrocyte sedimentation rate at least 30 mm/h.¹¹

RULE OUT INFECTION

If symptoms such as diarrhea or abdominal pain arise within 6 weeks of starting ICI therapy, then we should check for an infectious cause. The differential diagnosis of suspected ICI-associated colitis includes infections with C difficile, cytomegalovirus, opportunistic organisms, and other bacteria and viruses. ICI-induced celiac disease and immune hyper­thyroidism should also be ruled out.⁴

Once infection is ruled out, colonoscopy should be considered if symptoms persist or are severe. Colonoscopy with biopsy remains the gold standard for diagnosis, and it is also helpful in assessing severity of mucosal inflammation and monitoring response to medical treatment.

Table 2 lists common endoscopic and histologic features of ICI-mediated colitis; however, none of them is specific for this disease.

Common endoscopic features are loss of vascular pattern, edema, friability, spontaneous bleeding, and deep ulcerations.¹² A recent study suggested that colonic ulcerations predict a steroid-refractory course in patients with immune-mediated colitis.⁴

Histologically, ICI-associated colitis is characterized by both acute and chronic changes, including an increased number of neutrophils and lymphocytes in the epithelium and lamina propria, erosions, ulcers, crypt abscess, crypt apoptosis, crypt distortion, and even noncaseating granulomas.¹³ However, transmural disease is rare. Figure 2 compares the histopathologic features of ICI-associated colitis and a normal colon.

COMPUTED TOMOGRAPHY CAN BE USEFUL

Computed tomography (CT) can also be useful for the diagnosis and measurement of severity.

Garcia-Neuer et al1⁴ analyzed 303 patients with advanced melanoma who developed gastrointestinal symptoms while being treated with ipilimumab. Ninety-nine (33%) of them reported diarrhea during therapy, of whom 34 underwent both CT and colonoscopy with biopsy. CT was highly predictive of colitis on biopsy, with a positive predictive value of 96% and a negative likelihood ratio of 0.2.¹⁴

TREATMENT

Supportive care may be enough when treating mild ICI-related colitis. This can include oral and intravenous hydration⁴ and an antidiarrheal drug such as loperamide in a low dose.

Corticosteroids. For moderate ICI-associated colitis with stool frequency of 4 or more per day, patients should be started on an oral corticosteroid such as prednisone 0.5 to 1 mg/kg per day. If symptoms do not improve within 72 hours of starting an oral corticosteroid, the patient should be admitted to the hospital for observation and escalation to higher doses or possibly intravenous corticosteroids.

Infliximab has been used in severe and steroid-refractory cases,¹³ although there has been concern about using anti-tumor necrosis factor (TNF) agents such as this in patients with malignancies, especially melanoma. Since melanoma can be very aggressive and anti-TNF agents may promote it, it is prudent to try not to use this class of agents.

Other biologic agents such as vedolizu­mab, a gut-specific anti-integrin agent, are safer, have theoretic advantages over anti-TNF agents, and can be considered in patients with steroid-dependent or steroid-refractory ICI-associated enterocolitis. A recent study suggested that 2 to 4 infusions of vedolizumab are adequate to achieve steroid-free remission.¹⁵ Results from 6 clinical trials of vedolizumab in 2,830 patients with Crohn disease or ulcerative colitis did not show any increased risk of serious infections or malignancies over placebo.^16,17 A drawback is its slow onset of action.

Surgery is an option for patients with severe colitis refractory to intravenous corticosteroids or biological agents, as severe colitis carries a risk of significant morbidity and even death. The incidence of bowel perforation leading to colectomy or death in patients receiving ICI therapy is 0.5% to 1%.^18,19

Fecal microbiota transplant was associated with mucosal healing after 1 month in a case report of ICI-associated colitis.⁹

Follow-up. In most patients, symptoms resolve with discontinuation of the ICI and brief use of corticosteroids or biological agents. Patients with recurrent or persistent symptoms while on long-term ICI therapy may need periodic endoscopic evaluation, especially if there are chronic structural changes on histologic study.

If patients have recurrent or persistent symptoms along with chronic inflammatory structural changes on histology, a sign of an inflammatory bowel diseaselike condition, long-term maintenance therapy with an anti-inflammatory or immunosuppressant agent may be considered. However, there is no consensus on the treatment of this condition. It can be treated in the same way as classic inflammatory bowel disease in the setting of concurrent or prior history of malignancy, especially melanoma. Certain agents used in inflammatory bowel disease such as methotrexate and vedolizumab carry a lower risk of malignancy than anti-TNF agents and can be considered. A multidisciplinary approach that includes an oncologist, gastroenterologist, infectious disease specialist, and colorectal surgeon is imperative.

An 88-year-old man with a 1-day history of fever and altered mental status was transferred to the emergency department. He had been receiving conservative management for low-risk localized prostate cancer but had no previous cardiovascular or gastrointestinal problems.

Based on these findings, the diagnosis was Fournier gangrene. Despite aggressive treatment, the patient’s condition deteriorated rapidly, and he died 2 hours after admission.

FOURNIER GANGRENE: NECROTIZING FASCIITIS OF THE PERINEUM

Fournier gangrene is a rare but rapidly progressive necrotizing fasciitis of the perineum with a high death rate.

Predisposing factors for Fournier gangrene include older age, diabetes mellitus, morbid obesity, cardiovascular disorders, chronic alcoholism, long-term corticosteroid treatment, malignancy, and human immunodeficiency virus infection.^1,2 Urethral obstruction, instrumentation, urinary extravasation, and trauma have also been associated with this condition.³

In general, organisms from the urinary tract spread along the fascial planes to involve the penis and scrotum.

The differential diagnosis of Fournier gangrene includes scrotal and perineal disorders, as well as intra-abdominal disorders such as cellulitis, abscess, strangulated hernia, pyoderma gangrenosum, allergic vasculitis, vascular occlusion syndromes, and warfarin necrosis.

Delay in the diagnosis of Fournier gangrene leads to an extremely high death rate due to rapid progression of the disease, leading to sepsis, multiple organ failure, and disseminated intravascular coagulation. Immediate diagnosis and appropriate treatment such as broad-spectrum antibiotics and extensive surgical debridement reduce morbidity and control the infection. Antibiotics for methicillin-resistant Staphylococcus aureus should be considered if there is a history of or risk factors for this organism.⁴

Necrotizing fasciitis, including Fournier gangrene, is a common indication for intravenous immunoglobulin, and this treatment has been reported to be effective in a few cases. However, a double-blind, placebo-controlled trial that evaluated the benefit of this treatment was terminated early due to slow patient recruitment.⁵

A delay of even a few hours from suspicion of Fournier gangrene to surgical debridement significantly increases the risk of death.⁶ Thus, when it is suspected, immediate surgical intervention may be necessary to confirm the diagnosis and to treat it. The usual combination of antibiotic therapy for Fournier gangrene includes penicillin for the streptococcal species, a third-generation cephalosporin with or without an aminoglycoside for the gram-negative organisms, and metronidazole for anaerobic bacteria.

An 88-year-old man with a 1-day history of fever and altered mental status was transferred to the emergency department. He had been receiving conservative management for low-risk localized prostate cancer but had no previous cardiovascular or gastrointestinal problems.

Based on these findings, the diagnosis was Fournier gangrene. Despite aggressive treatment, the patient’s condition deteriorated rapidly, and he died 2 hours after admission.

FOURNIER GANGRENE: NECROTIZING FASCIITIS OF THE PERINEUM

Fournier gangrene is a rare but rapidly progressive necrotizing fasciitis of the perineum with a high death rate.

Predisposing factors for Fournier gangrene include older age, diabetes mellitus, morbid obesity, cardiovascular disorders, chronic alcoholism, long-term corticosteroid treatment, malignancy, and human immunodeficiency virus infection.^1,2 Urethral obstruction, instrumentation, urinary extravasation, and trauma have also been associated with this condition.³

In general, organisms from the urinary tract spread along the fascial planes to involve the penis and scrotum.

The differential diagnosis of Fournier gangrene includes scrotal and perineal disorders, as well as intra-abdominal disorders such as cellulitis, abscess, strangulated hernia, pyoderma gangrenosum, allergic vasculitis, vascular occlusion syndromes, and warfarin necrosis.

Delay in the diagnosis of Fournier gangrene leads to an extremely high death rate due to rapid progression of the disease, leading to sepsis, multiple organ failure, and disseminated intravascular coagulation. Immediate diagnosis and appropriate treatment such as broad-spectrum antibiotics and extensive surgical debridement reduce morbidity and control the infection. Antibiotics for methicillin-resistant Staphylococcus aureus should be considered if there is a history of or risk factors for this organism.⁴

Necrotizing fasciitis, including Fournier gangrene, is a common indication for intravenous immunoglobulin, and this treatment has been reported to be effective in a few cases. However, a double-blind, placebo-controlled trial that evaluated the benefit of this treatment was terminated early due to slow patient recruitment.⁵

A delay of even a few hours from suspicion of Fournier gangrene to surgical debridement significantly increases the risk of death.⁶ Thus, when it is suspected, immediate surgical intervention may be necessary to confirm the diagnosis and to treat it. The usual combination of antibiotic therapy for Fournier gangrene includes penicillin for the streptococcal species, a third-generation cephalosporin with or without an aminoglycoside for the gram-negative organisms, and metronidazole for anaerobic bacteria.

An 88-year-old man with a 1-day history of fever and altered mental status was transferred to the emergency department. He had been receiving conservative management for low-risk localized prostate cancer but had no previous cardiovascular or gastrointestinal problems.

Based on these findings, the diagnosis was Fournier gangrene. Despite aggressive treatment, the patient’s condition deteriorated rapidly, and he died 2 hours after admission.

FOURNIER GANGRENE: NECROTIZING FASCIITIS OF THE PERINEUM

Fournier gangrene is a rare but rapidly progressive necrotizing fasciitis of the perineum with a high death rate.

Predisposing factors for Fournier gangrene include older age, diabetes mellitus, morbid obesity, cardiovascular disorders, chronic alcoholism, long-term corticosteroid treatment, malignancy, and human immunodeficiency virus infection.^1,2 Urethral obstruction, instrumentation, urinary extravasation, and trauma have also been associated with this condition.³

In general, organisms from the urinary tract spread along the fascial planes to involve the penis and scrotum.

The differential diagnosis of Fournier gangrene includes scrotal and perineal disorders, as well as intra-abdominal disorders such as cellulitis, abscess, strangulated hernia, pyoderma gangrenosum, allergic vasculitis, vascular occlusion syndromes, and warfarin necrosis.

Delay in the diagnosis of Fournier gangrene leads to an extremely high death rate due to rapid progression of the disease, leading to sepsis, multiple organ failure, and disseminated intravascular coagulation. Immediate diagnosis and appropriate treatment such as broad-spectrum antibiotics and extensive surgical debridement reduce morbidity and control the infection. Antibiotics for methicillin-resistant Staphylococcus aureus should be considered if there is a history of or risk factors for this organism.⁴

Necrotizing fasciitis, including Fournier gangrene, is a common indication for intravenous immunoglobulin, and this treatment has been reported to be effective in a few cases. However, a double-blind, placebo-controlled trial that evaluated the benefit of this treatment was terminated early due to slow patient recruitment.⁵

A delay of even a few hours from suspicion of Fournier gangrene to surgical debridement significantly increases the risk of death.⁶ Thus, when it is suspected, immediate surgical intervention may be necessary to confirm the diagnosis and to treat it. The usual combination of antibiotic therapy for Fournier gangrene includes penicillin for the streptococcal species, a third-generation cephalosporin with or without an aminoglycoside for the gram-negative organisms, and metronidazole for anaerobic bacteria.

A 60-year-old man with hypertension and persistent atrial fibrillation refractory to radiofrequency ablation was brought to the hospital in status epilepticus requiring intubation. His wife said that during the past month he had experienced a number of episodic seizures, but due to his busy work schedule he had not sought medical attention. He had also been hospitalized 3 times during the past week for chills, tremors, and fevers with temperatures up to 101°F (38.3°C), and his symptoms had been ascribed to the amiodarone he had been taking for the past 11 days for atrial fibrillation. The amiodarone dose had been decreased to half a tablet after the first 7 days, but his symptoms had continued.

When the patient was able to speak, he denied intravenous drug abuse and claimed to be up to date with vaccinations. Colonoscopy 10 years earlier had been negative. He has no pets, but says that there are stray cats around his home and that he has had contact with cat feces while gardening. He works as a diesel mechanic and is exposed to motor oil and diesel fuel, but denies any direct exposure to carcinogenic chemicals.

On admission, his temperature was 37.7°C (99.9°F), blood pressure 92/69 mm Hg, heart rate 96 beats per minute, respiratory rate 21 per minute, and oxygen saturation 95% on room air and 100% on oxygen at 2 L per minute.

Decerebrate posturing and forced left visual gaze deviation was observed. Oral examination revealed severe decay of multiple teeth, with some teeth broken down to the level of the gingiva, and moderate generalized periodontal disease with heavy plaque and calculi in the gingiva.

The differential diagnosis for intracranial ring-enhancing lesions includes metastasis, abscess, infection in an immunocompromised state (eg, toxoplasmosis), glioblastoma, subacute infarct, neurocysticercosis, lymphoma, demyelination, and resolving hematoma. In our patient, further testing to narrow the differential included lumbar puncture, with results within normal limits, and transthoracic echocardiography, which was negative for endocarditis. A biopsy obtained by craniotomy confirmed the diagnosis of abscess surrounded by reactive glioses.

During his hospitalization, the patient’s antiseizure regimen was lorazepam 1 to 2 mg as needed, levetiracetam 1,500 mg twice daily, and fosphenytoin infusion at 100 mg phenytoin sodium equivalents per minute. Initial antibiotic therapy included ampicillin 2 g intravenously (IV) 4 times daily.

Because of persistent nocturnal fevers with temperatures ranging from 37.8°C (100°F) to 41.2°C (106.2°F), antibiotic coverage was broadened to meropenem 2 g IV every 8 hours. Testing for Toxoplasma gondii, human immunodeficiency virus, and JC polyomavirus was negative. Cerebrospinal fluid culture and abscess cultures were also negative. Blood cultures were eventually positive for Peptostreptococcus micros and Streptococcus constellatus. Based on review of culture results, antibiotic therapy was switched to ceftriaxone 2 g IV twice daily and metronidazole 500 mg IV 3 times daily.

For the dental infection, the patient underwent surgical irrigation and debridement with full dental extraction for multiple dental abscesses.

His regimen for seizure control was changed to phenytoin and valproic acid, and he was discharged in stable condition on the following drug regimen: ceftriaxone 2 g IV twice daily, metronidazole 500 mg IV 3 times daily for 6 weeks, levetiracetam 1,500 mg twice daily, and valproic acid 750 mg 3 times daily.

At a 3-month follow-up visit, he reported no seizure-like activity but demonstrated persistent neurologic deficits (dysdiadocho­kinesia and mild ataxia).

A LESS COMMON CAUSE OF BRAIN ABSCESS

In the United States, 1,500 to 2,000 cases of brain abscess are diagnosed every year, and this condition is responsible for an estimated 1 in 10,000 hospitalizations. Most patients hospitalized are men over age 60 or children. Most patients with hematogenous or embolic spread of infection from a primary infection source are immunocompromised.

However, the lesions in our patient were not from compromised immunity, but rather from septic hematogenous spread of an odontogenic infection. Odontogenic bacteria are a common cause of pyogenic orofascial infection, including periapical abscess and infection of adjoining fascial spaces of the head and neck.¹

P micros and S constellatus have been commonly found in many types of odontogenic infection, including dentoalveolar infection, periodontitis, and pericoronitis.² Our patient was found to have several periodontal abscesses with bacteremia and spread to the brain. Although transthoracic echocardiography was negative for vegetations or patent foramen ovale, the quality and location of the brain abscesses suggested embolic spread of infection. Most of the suspected septic emboli were in the right hemisphere, consistent with patterns seen with cardioembolic phenomena, and a number of lesions appeared to be within the distribution of the right anterior cerebral artery and the middle cerebral artery.

Empiric antibiotic therapy for local odontogenic infection includes amoxicillin with clavulanic acid and metronidazole.¹ Our patient’s treatment with ceftriaxone and metronidazole was based on the species and sensitivities of the bacteria in blood cultures.

Surgical irrigation with debridement is considered first-line therapy for local dental infection, with antimicrobials as adjunctive therapy. Initiation of antibiotic therapy before surgery has been associated with a shortened duration of infection and a reduced risk of bacteremia.³

First-line therapy for cerebral abscess is typically antibiotics, specifically ceftriaxone and metronidazole as in our patient. Ceftriaxone is selected for coverage against streptococci, enterobacteriacae, and most common anaerobes, whereas metronidazole is chosen for its efficacy against Bacteroides fragilis.

Computed tomography-guided stereotactic aspiration and open drainage are viable options for solitary and surgically accessible abscesses—typically those greater than 2 cm. Our patient had multiple small septic emboli in the right hemisphere, with the largest lesion measuring 1.5 cm, thus limiting the effectiveness of surgical intervention.

Some patients with mass effect or other evidence of increased intracranial pressure may benefit from high doses of a corticosteroid such as dexamethasone. However, since our patient had no clinical or diagnostic findings suggesting elevated intracranial pressure, we opted for nonsurgical management of the brain abscesses, with 6 weeks of intravenous antibiotics, an antiseizure regimen, and plans for repeat imaging in the outpatient setting.

A 60-year-old man with hypertension and persistent atrial fibrillation refractory to radiofrequency ablation was brought to the hospital in status epilepticus requiring intubation. His wife said that during the past month he had experienced a number of episodic seizures, but due to his busy work schedule he had not sought medical attention. He had also been hospitalized 3 times during the past week for chills, tremors, and fevers with temperatures up to 101°F (38.3°C), and his symptoms had been ascribed to the amiodarone he had been taking for the past 11 days for atrial fibrillation. The amiodarone dose had been decreased to half a tablet after the first 7 days, but his symptoms had continued.

When the patient was able to speak, he denied intravenous drug abuse and claimed to be up to date with vaccinations. Colonoscopy 10 years earlier had been negative. He has no pets, but says that there are stray cats around his home and that he has had contact with cat feces while gardening. He works as a diesel mechanic and is exposed to motor oil and diesel fuel, but denies any direct exposure to carcinogenic chemicals.

On admission, his temperature was 37.7°C (99.9°F), blood pressure 92/69 mm Hg, heart rate 96 beats per minute, respiratory rate 21 per minute, and oxygen saturation 95% on room air and 100% on oxygen at 2 L per minute.

Decerebrate posturing and forced left visual gaze deviation was observed. Oral examination revealed severe decay of multiple teeth, with some teeth broken down to the level of the gingiva, and moderate generalized periodontal disease with heavy plaque and calculi in the gingiva.

The differential diagnosis for intracranial ring-enhancing lesions includes metastasis, abscess, infection in an immunocompromised state (eg, toxoplasmosis), glioblastoma, subacute infarct, neurocysticercosis, lymphoma, demyelination, and resolving hematoma. In our patient, further testing to narrow the differential included lumbar puncture, with results within normal limits, and transthoracic echocardiography, which was negative for endocarditis. A biopsy obtained by craniotomy confirmed the diagnosis of abscess surrounded by reactive glioses.

During his hospitalization, the patient’s antiseizure regimen was lorazepam 1 to 2 mg as needed, levetiracetam 1,500 mg twice daily, and fosphenytoin infusion at 100 mg phenytoin sodium equivalents per minute. Initial antibiotic therapy included ampicillin 2 g intravenously (IV) 4 times daily.

Because of persistent nocturnal fevers with temperatures ranging from 37.8°C (100°F) to 41.2°C (106.2°F), antibiotic coverage was broadened to meropenem 2 g IV every 8 hours. Testing for Toxoplasma gondii, human immunodeficiency virus, and JC polyomavirus was negative. Cerebrospinal fluid culture and abscess cultures were also negative. Blood cultures were eventually positive for Peptostreptococcus micros and Streptococcus constellatus. Based on review of culture results, antibiotic therapy was switched to ceftriaxone 2 g IV twice daily and metronidazole 500 mg IV 3 times daily.

For the dental infection, the patient underwent surgical irrigation and debridement with full dental extraction for multiple dental abscesses.

His regimen for seizure control was changed to phenytoin and valproic acid, and he was discharged in stable condition on the following drug regimen: ceftriaxone 2 g IV twice daily, metronidazole 500 mg IV 3 times daily for 6 weeks, levetiracetam 1,500 mg twice daily, and valproic acid 750 mg 3 times daily.

At a 3-month follow-up visit, he reported no seizure-like activity but demonstrated persistent neurologic deficits (dysdiadocho­kinesia and mild ataxia).

A LESS COMMON CAUSE OF BRAIN ABSCESS

In the United States, 1,500 to 2,000 cases of brain abscess are diagnosed every year, and this condition is responsible for an estimated 1 in 10,000 hospitalizations. Most patients hospitalized are men over age 60 or children. Most patients with hematogenous or embolic spread of infection from a primary infection source are immunocompromised.

However, the lesions in our patient were not from compromised immunity, but rather from septic hematogenous spread of an odontogenic infection. Odontogenic bacteria are a common cause of pyogenic orofascial infection, including periapical abscess and infection of adjoining fascial spaces of the head and neck.¹

P micros and S constellatus have been commonly found in many types of odontogenic infection, including dentoalveolar infection, periodontitis, and pericoronitis.² Our patient was found to have several periodontal abscesses with bacteremia and spread to the brain. Although transthoracic echocardiography was negative for vegetations or patent foramen ovale, the quality and location of the brain abscesses suggested embolic spread of infection. Most of the suspected septic emboli were in the right hemisphere, consistent with patterns seen with cardioembolic phenomena, and a number of lesions appeared to be within the distribution of the right anterior cerebral artery and the middle cerebral artery.

Empiric antibiotic therapy for local odontogenic infection includes amoxicillin with clavulanic acid and metronidazole.¹ Our patient’s treatment with ceftriaxone and metronidazole was based on the species and sensitivities of the bacteria in blood cultures.

Surgical irrigation with debridement is considered first-line therapy for local dental infection, with antimicrobials as adjunctive therapy. Initiation of antibiotic therapy before surgery has been associated with a shortened duration of infection and a reduced risk of bacteremia.³

First-line therapy for cerebral abscess is typically antibiotics, specifically ceftriaxone and metronidazole as in our patient. Ceftriaxone is selected for coverage against streptococci, enterobacteriacae, and most common anaerobes, whereas metronidazole is chosen for its efficacy against Bacteroides fragilis.

Computed tomography-guided stereotactic aspiration and open drainage are viable options for solitary and surgically accessible abscesses—typically those greater than 2 cm. Our patient had multiple small septic emboli in the right hemisphere, with the largest lesion measuring 1.5 cm, thus limiting the effectiveness of surgical intervention.

Some patients with mass effect or other evidence of increased intracranial pressure may benefit from high doses of a corticosteroid such as dexamethasone. However, since our patient had no clinical or diagnostic findings suggesting elevated intracranial pressure, we opted for nonsurgical management of the brain abscesses, with 6 weeks of intravenous antibiotics, an antiseizure regimen, and plans for repeat imaging in the outpatient setting.

A 60-year-old man with hypertension and persistent atrial fibrillation refractory to radiofrequency ablation was brought to the hospital in status epilepticus requiring intubation. His wife said that during the past month he had experienced a number of episodic seizures, but due to his busy work schedule he had not sought medical attention. He had also been hospitalized 3 times during the past week for chills, tremors, and fevers with temperatures up to 101°F (38.3°C), and his symptoms had been ascribed to the amiodarone he had been taking for the past 11 days for atrial fibrillation. The amiodarone dose had been decreased to half a tablet after the first 7 days, but his symptoms had continued.

When the patient was able to speak, he denied intravenous drug abuse and claimed to be up to date with vaccinations. Colonoscopy 10 years earlier had been negative. He has no pets, but says that there are stray cats around his home and that he has had contact with cat feces while gardening. He works as a diesel mechanic and is exposed to motor oil and diesel fuel, but denies any direct exposure to carcinogenic chemicals.

On admission, his temperature was 37.7°C (99.9°F), blood pressure 92/69 mm Hg, heart rate 96 beats per minute, respiratory rate 21 per minute, and oxygen saturation 95% on room air and 100% on oxygen at 2 L per minute.

Decerebrate posturing and forced left visual gaze deviation was observed. Oral examination revealed severe decay of multiple teeth, with some teeth broken down to the level of the gingiva, and moderate generalized periodontal disease with heavy plaque and calculi in the gingiva.

The differential diagnosis for intracranial ring-enhancing lesions includes metastasis, abscess, infection in an immunocompromised state (eg, toxoplasmosis), glioblastoma, subacute infarct, neurocysticercosis, lymphoma, demyelination, and resolving hematoma. In our patient, further testing to narrow the differential included lumbar puncture, with results within normal limits, and transthoracic echocardiography, which was negative for endocarditis. A biopsy obtained by craniotomy confirmed the diagnosis of abscess surrounded by reactive glioses.

During his hospitalization, the patient’s antiseizure regimen was lorazepam 1 to 2 mg as needed, levetiracetam 1,500 mg twice daily, and fosphenytoin infusion at 100 mg phenytoin sodium equivalents per minute. Initial antibiotic therapy included ampicillin 2 g intravenously (IV) 4 times daily.

Because of persistent nocturnal fevers with temperatures ranging from 37.8°C (100°F) to 41.2°C (106.2°F), antibiotic coverage was broadened to meropenem 2 g IV every 8 hours. Testing for Toxoplasma gondii, human immunodeficiency virus, and JC polyomavirus was negative. Cerebrospinal fluid culture and abscess cultures were also negative. Blood cultures were eventually positive for Peptostreptococcus micros and Streptococcus constellatus. Based on review of culture results, antibiotic therapy was switched to ceftriaxone 2 g IV twice daily and metronidazole 500 mg IV 3 times daily.

For the dental infection, the patient underwent surgical irrigation and debridement with full dental extraction for multiple dental abscesses.

His regimen for seizure control was changed to phenytoin and valproic acid, and he was discharged in stable condition on the following drug regimen: ceftriaxone 2 g IV twice daily, metronidazole 500 mg IV 3 times daily for 6 weeks, levetiracetam 1,500 mg twice daily, and valproic acid 750 mg 3 times daily.

At a 3-month follow-up visit, he reported no seizure-like activity but demonstrated persistent neurologic deficits (dysdiadocho­kinesia and mild ataxia).

A LESS COMMON CAUSE OF BRAIN ABSCESS

In the United States, 1,500 to 2,000 cases of brain abscess are diagnosed every year, and this condition is responsible for an estimated 1 in 10,000 hospitalizations. Most patients hospitalized are men over age 60 or children. Most patients with hematogenous or embolic spread of infection from a primary infection source are immunocompromised.

However, the lesions in our patient were not from compromised immunity, but rather from septic hematogenous spread of an odontogenic infection. Odontogenic bacteria are a common cause of pyogenic orofascial infection, including periapical abscess and infection of adjoining fascial spaces of the head and neck.¹

P micros and S constellatus have been commonly found in many types of odontogenic infection, including dentoalveolar infection, periodontitis, and pericoronitis.² Our patient was found to have several periodontal abscesses with bacteremia and spread to the brain. Although transthoracic echocardiography was negative for vegetations or patent foramen ovale, the quality and location of the brain abscesses suggested embolic spread of infection. Most of the suspected septic emboli were in the right hemisphere, consistent with patterns seen with cardioembolic phenomena, and a number of lesions appeared to be within the distribution of the right anterior cerebral artery and the middle cerebral artery.

Empiric antibiotic therapy for local odontogenic infection includes amoxicillin with clavulanic acid and metronidazole.¹ Our patient’s treatment with ceftriaxone and metronidazole was based on the species and sensitivities of the bacteria in blood cultures.

Surgical irrigation with debridement is considered first-line therapy for local dental infection, with antimicrobials as adjunctive therapy. Initiation of antibiotic therapy before surgery has been associated with a shortened duration of infection and a reduced risk of bacteremia.³

First-line therapy for cerebral abscess is typically antibiotics, specifically ceftriaxone and metronidazole as in our patient. Ceftriaxone is selected for coverage against streptococci, enterobacteriacae, and most common anaerobes, whereas metronidazole is chosen for its efficacy against Bacteroides fragilis.

Computed tomography-guided stereotactic aspiration and open drainage are viable options for solitary and surgically accessible abscesses—typically those greater than 2 cm. Our patient had multiple small septic emboli in the right hemisphere, with the largest lesion measuring 1.5 cm, thus limiting the effectiveness of surgical intervention.

Some patients with mass effect or other evidence of increased intracranial pressure may benefit from high doses of a corticosteroid such as dexamethasone. However, since our patient had no clinical or diagnostic findings suggesting elevated intracranial pressure, we opted for nonsurgical management of the brain abscesses, with 6 weeks of intravenous antibiotics, an antiseizure regimen, and plans for repeat imaging in the outpatient setting.

Some drugs exhibit a dose-toxicity relationship that is sufficiently predictable to permit drug-level monitoring to limit renal or other toxicity. Others cause ocular or marrow toxicity that can be limited by weight-based dosing and careful monitoring. With azathioprine, some toxicity can be predicted by assessing the activity of the enzyme thiopurine methyltransferase, which metabolizes the drug. Other approaches to using pharmacogenomics have included HLA-B locus haplotyping to detect increased risk of immune-mediated toxicities of drugs such as carbamazepine and allopurinol. Both of these drugs exhibit serious systemic toxicities that are incompletely understood, but these are nascent and significant steps toward providing personalized (precision) medical care.

Adverse effects of some drugs may result from their intracellular effects, which are only partially predictable by drug levels or dosing. Colchicine, hydroxychloroquine, and amiodarone all affect intracellular vacuolar transport and lysosomal processing. Yet, although the footprints of drug effect can be seen in many histopathology samples, only some patients—but maybe more than currently recognized—suffer cardiac and skeletal muscle vacuolar myopathy, axonal neuropathies, or pulmonary or retinal cell toxicity from these drugs. But distinguishing the histopathologic footprints of drug exposure and the biologic effect from true drug toxicity with organ damage is not always straightforward.

Rare adverse effects may only become apparent with frequent use of a drug in the general community. These often remain mechanistically unexplained: Why can minoxidil cause pericardial effusions or a nonsteroidal anti-inflammatory drug cause aseptic meningitis? Some effects may be due to altering of the unique balance of biochemical pathways in a given patient, leading to unexpected drug metabolism with generation of toxic metabolites.

More interesting to me are effects that are seemingly off-target biologic outcomes caused by disrupting normal physiologic homeostasis and stimulating counterregulatory pathways in such a way that unexpected biologic effects occur. Angioedema and cough in some patients who have taken angiotensin-converting enzyme inhibitors are examples, but why the disturbed control mechanisms lead to these effects in only occasional patients is still incompletely elucidated.

Two additional classes of drugs with unique systemic adverse effects are discussed in this issue of the Journal. The “flulike” syndrome after bisphosphonate treatment, presumably resulting from selective cytokine release by macrophages that have ingested certain bisphosphonates, is a not uncommon and significant annoyance to many patients, and in my experience it is a reason patients discontinue the treatment. Lim and Bolster describe the reaction and their approach to its management, and comment on the fairly obscure pathway that may explain its occurrence. Again, it is not clear to me why only relatively few patients experience the reaction. Is there a genetic predisposition? Or is it influenced by the patient’s baseline “inflammatory tone,” as influenced by the state of his or her microbiome or other still uncharacterized factors? And why does this reaction often diminish with repeated dosing of the drug?

Most striking is the description and discussion by Khan et al of the management of autoimmune colitis after administration of immune checkpoint inhibitor anticancer therapies. These drugs represent important advances in the therapy of various cancers. They are novel in that they are not specific to tumor type, although certain drugs within this new class of immunotherapy seem to exhibit more dramatic and enduring responses against one type of cancer than against another. These therapies are not directly tumor-reactive, but act by down-regulating the normal “brakes” or checkpoints of the immune system that normally play a role in reigning in the immune-inflammatory system response to infection once the offending infective agent is neutralized. These checkpoints have also been thought to limit the development of autoimmunity. Many cancers seem to capitalize on the activation of these brakes to evade tumor immunity. That these checkpoint therapies are so effective in some patients with heretofore unresponsive cancers is obviously a major advance. But equally striking is the scientific proof of the immunologic concept that by inhibiting these normal brakes on inflammation there is loss of normal regulation of the immune response and autoimmunity ensues unchecked. Khan et al discuss the colitis that can occur with these therapies, but a host of fascinating and potentially life-threatening organ-specific complications can be invoked by the checkpoint inhibitors, including hypophysitis, myositis, nephritis, and pneumonitis. What determines which patient will suffer these immune complications, which organs will be affected in a given patient, and the relationships between preexisting autoimmune disease, antitumor response, and these autoimmune complications are still being unraveled.

If you have not yet encountered patients with these complications in your practice, it is quite likely you will. The topic is worth reading about now (see the review by June et al¹), and we will provide additional reviews in the future.

Some drugs exhibit a dose-toxicity relationship that is sufficiently predictable to permit drug-level monitoring to limit renal or other toxicity. Others cause ocular or marrow toxicity that can be limited by weight-based dosing and careful monitoring. With azathioprine, some toxicity can be predicted by assessing the activity of the enzyme thiopurine methyltransferase, which metabolizes the drug. Other approaches to using pharmacogenomics have included HLA-B locus haplotyping to detect increased risk of immune-mediated toxicities of drugs such as carbamazepine and allopurinol. Both of these drugs exhibit serious systemic toxicities that are incompletely understood, but these are nascent and significant steps toward providing personalized (precision) medical care.

Adverse effects of some drugs may result from their intracellular effects, which are only partially predictable by drug levels or dosing. Colchicine, hydroxychloroquine, and amiodarone all affect intracellular vacuolar transport and lysosomal processing. Yet, although the footprints of drug effect can be seen in many histopathology samples, only some patients—but maybe more than currently recognized—suffer cardiac and skeletal muscle vacuolar myopathy, axonal neuropathies, or pulmonary or retinal cell toxicity from these drugs. But distinguishing the histopathologic footprints of drug exposure and the biologic effect from true drug toxicity with organ damage is not always straightforward.

Rare adverse effects may only become apparent with frequent use of a drug in the general community. These often remain mechanistically unexplained: Why can minoxidil cause pericardial effusions or a nonsteroidal anti-inflammatory drug cause aseptic meningitis? Some effects may be due to altering of the unique balance of biochemical pathways in a given patient, leading to unexpected drug metabolism with generation of toxic metabolites.

More interesting to me are effects that are seemingly off-target biologic outcomes caused by disrupting normal physiologic homeostasis and stimulating counterregulatory pathways in such a way that unexpected biologic effects occur. Angioedema and cough in some patients who have taken angiotensin-converting enzyme inhibitors are examples, but why the disturbed control mechanisms lead to these effects in only occasional patients is still incompletely elucidated.

Two additional classes of drugs with unique systemic adverse effects are discussed in this issue of the Journal. The “flulike” syndrome after bisphosphonate treatment, presumably resulting from selective cytokine release by macrophages that have ingested certain bisphosphonates, is a not uncommon and significant annoyance to many patients, and in my experience it is a reason patients discontinue the treatment. Lim and Bolster describe the reaction and their approach to its management, and comment on the fairly obscure pathway that may explain its occurrence. Again, it is not clear to me why only relatively few patients experience the reaction. Is there a genetic predisposition? Or is it influenced by the patient’s baseline “inflammatory tone,” as influenced by the state of his or her microbiome or other still uncharacterized factors? And why does this reaction often diminish with repeated dosing of the drug?

Most striking is the description and discussion by Khan et al of the management of autoimmune colitis after administration of immune checkpoint inhibitor anticancer therapies. These drugs represent important advances in the therapy of various cancers. They are novel in that they are not specific to tumor type, although certain drugs within this new class of immunotherapy seem to exhibit more dramatic and enduring responses against one type of cancer than against another. These therapies are not directly tumor-reactive, but act by down-regulating the normal “brakes” or checkpoints of the immune system that normally play a role in reigning in the immune-inflammatory system response to infection once the offending infective agent is neutralized. These checkpoints have also been thought to limit the development of autoimmunity. Many cancers seem to capitalize on the activation of these brakes to evade tumor immunity. That these checkpoint therapies are so effective in some patients with heretofore unresponsive cancers is obviously a major advance. But equally striking is the scientific proof of the immunologic concept that by inhibiting these normal brakes on inflammation there is loss of normal regulation of the immune response and autoimmunity ensues unchecked. Khan et al discuss the colitis that can occur with these therapies, but a host of fascinating and potentially life-threatening organ-specific complications can be invoked by the checkpoint inhibitors, including hypophysitis, myositis, nephritis, and pneumonitis. What determines which patient will suffer these immune complications, which organs will be affected in a given patient, and the relationships between preexisting autoimmune disease, antitumor response, and these autoimmune complications are still being unraveled.

If you have not yet encountered patients with these complications in your practice, it is quite likely you will. The topic is worth reading about now (see the review by June et al¹), and we will provide additional reviews in the future.

Some drugs exhibit a dose-toxicity relationship that is sufficiently predictable to permit drug-level monitoring to limit renal or other toxicity. Others cause ocular or marrow toxicity that can be limited by weight-based dosing and careful monitoring. With azathioprine, some toxicity can be predicted by assessing the activity of the enzyme thiopurine methyltransferase, which metabolizes the drug. Other approaches to using pharmacogenomics have included HLA-B locus haplotyping to detect increased risk of immune-mediated toxicities of drugs such as carbamazepine and allopurinol. Both of these drugs exhibit serious systemic toxicities that are incompletely understood, but these are nascent and significant steps toward providing personalized (precision) medical care.

Adverse effects of some drugs may result from their intracellular effects, which are only partially predictable by drug levels or dosing. Colchicine, hydroxychloroquine, and amiodarone all affect intracellular vacuolar transport and lysosomal processing. Yet, although the footprints of drug effect can be seen in many histopathology samples, only some patients—but maybe more than currently recognized—suffer cardiac and skeletal muscle vacuolar myopathy, axonal neuropathies, or pulmonary or retinal cell toxicity from these drugs. But distinguishing the histopathologic footprints of drug exposure and the biologic effect from true drug toxicity with organ damage is not always straightforward.

Rare adverse effects may only become apparent with frequent use of a drug in the general community. These often remain mechanistically unexplained: Why can minoxidil cause pericardial effusions or a nonsteroidal anti-inflammatory drug cause aseptic meningitis? Some effects may be due to altering of the unique balance of biochemical pathways in a given patient, leading to unexpected drug metabolism with generation of toxic metabolites.

More interesting to me are effects that are seemingly off-target biologic outcomes caused by disrupting normal physiologic homeostasis and stimulating counterregulatory pathways in such a way that unexpected biologic effects occur. Angioedema and cough in some patients who have taken angiotensin-converting enzyme inhibitors are examples, but why the disturbed control mechanisms lead to these effects in only occasional patients is still incompletely elucidated.

Two additional classes of drugs with unique systemic adverse effects are discussed in this issue of the Journal. The “flulike” syndrome after bisphosphonate treatment, presumably resulting from selective cytokine release by macrophages that have ingested certain bisphosphonates, is a not uncommon and significant annoyance to many patients, and in my experience it is a reason patients discontinue the treatment. Lim and Bolster describe the reaction and their approach to its management, and comment on the fairly obscure pathway that may explain its occurrence. Again, it is not clear to me why only relatively few patients experience the reaction. Is there a genetic predisposition? Or is it influenced by the patient’s baseline “inflammatory tone,” as influenced by the state of his or her microbiome or other still uncharacterized factors? And why does this reaction often diminish with repeated dosing of the drug?

Most striking is the description and discussion by Khan et al of the management of autoimmune colitis after administration of immune checkpoint inhibitor anticancer therapies. These drugs represent important advances in the therapy of various cancers. They are novel in that they are not specific to tumor type, although certain drugs within this new class of immunotherapy seem to exhibit more dramatic and enduring responses against one type of cancer than against another. These therapies are not directly tumor-reactive, but act by down-regulating the normal “brakes” or checkpoints of the immune system that normally play a role in reigning in the immune-inflammatory system response to infection once the offending infective agent is neutralized. These checkpoints have also been thought to limit the development of autoimmunity. Many cancers seem to capitalize on the activation of these brakes to evade tumor immunity. That these checkpoint therapies are so effective in some patients with heretofore unresponsive cancers is obviously a major advance. But equally striking is the scientific proof of the immunologic concept that by inhibiting these normal brakes on inflammation there is loss of normal regulation of the immune response and autoimmunity ensues unchecked. Khan et al discuss the colitis that can occur with these therapies, but a host of fascinating and potentially life-threatening organ-specific complications can be invoked by the checkpoint inhibitors, including hypophysitis, myositis, nephritis, and pneumonitis. What determines which patient will suffer these immune complications, which organs will be affected in a given patient, and the relationships between preexisting autoimmune disease, antitumor response, and these autoimmune complications are still being unraveled.

If you have not yet encountered patients with these complications in your practice, it is quite likely you will. The topic is worth reading about now (see the review by June et al¹), and we will provide additional reviews in the future.

An 87-year-old woman was brought to the intensive care unit with worsening shortness of breath on exertion, fatigue, orthopnea, paroxysmal nocturnal dyspnea, lower extremity swelling, subjective fever, productive cough, and rhinorrhea over the last week. She reported no chest pain, lightheadedness, or palpitations. Her medical history included the following:

• Coronary artery disease requiring coronary artery bypass grafting
• Ischemic cardiomyopathy
• Severe mitral regurgitation
• Moderate tricuspid regurgitation
• Pulmonary hypertension
• Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
• Hypothyroidism requiring levothyroxine
• Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
• Long-standing essential thrombocythemia treated with hydroxyurea.

Before admission, she had been reliably taking guideline-directed heart failure therapy as well as amiodarone for her recurrent ventricular tachycardia. Her levothyroxine had recently been increased as well.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

• Acute decompensated heart failure
• Pulmonary embolism
• Exacerbation of asthma
• Exacerbation of chronic obstructive pulmonary disease (COPD)

Heart failure is a clinical diagnosis based on careful history-taking and physical examination. Major criteria include paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary crackles, a third heart sound, cardiomegaly, pulmonary edema, and weight loss of more than 4.5 kg with diuretic therapy.¹ N-terminal pro-B-type natriuretic peptide (NT-proBNP) is also an effective marker of acute decompensated heart failure in the proper clinical setting.²

Our patient’s elevated jugular venous pressure, bibasilar crackles, lower extremity edema, chest radiography findings consistent with pulmonary edema, markedly elevated NT-proBNP, history of orthopnea, paroxysmal nocturnal dyspnea, and dyspnea on exertion were most consistent with acute decompensated heart failure. Her cough and subjective fevers were thought to be due to an upper respiratory tract viral infection.

Pulmonary embolism causes pleuritic chest pain, dyspnea, and, occasionally, elevated troponin. The most common feature on electrocardiography is sinus tachycardia; nonspecific ST-segment and T-wave changes may also be seen.³

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

Although our patient presented with cough and dyspnea, she had no history of COPD and her other signs and symptoms (elevated jugular venous pressure, elevated NT-proBNP, and peripheral edema) could not be explained by COPD exacerbation.

Echocardiography revealed severe left ventricular enlargement, an ejection fraction of 20% (which was near her baseline value), diffuse regional wall-motion abnormalities, severe mitral regurgitation, and moderate tricuspid regurgitation consistent with an exacerbation of heart failure.

We considered the possibility that her heart failure symptoms might be due to precipitous up-titration of her levothyroxine dose, given her borderline-elevated free thyroxine (T₄) and increase in cardiac index (currently 4.45 L/min/m², previously 2.20 L/min/m² by the left ventricular outflow tract velocity time integral method). However, given her reduced ejection fraction, this clinical presentation most likely represented an acute exacerbation of her chronic heart failure. Her subjective fevers were thought to be due to a viral infection of the upper respiratory tract. The macrocytic anemia and thrombocytopenia were thought to be a side effect of her long-standing treatment with hydroxyurea for essential thrombocythemia, although amiodarone has also been associated with cytopenia.⁸

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

Further testing for connective tissue disease and hypersensitivity pneumonitis was also done, and the results were negative. To exclude an atypical infection, bronchoalveolar lavage was performed; preliminary microbial testing was negative, and the white blood cell count in the lavage fluid was 90% macrophages (pigment-laden), 7% neutrophils, and 3% lymphocytes.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

• Heart failure with reduced ejection fraction
• Bacterial pneumonia
• Idiopathic pulmonary fibrosis
• Amiodarone pulmonary toxicity

Heart failure with reduced ejection fraction can cause ground-glass opacities on CT due to increased pulmonary edema. Although our patient initially presented with acute decompensation of heart failure with reduced ejection fraction decompensation, she had returned to euvolemia after aggressive diuresis. Moreover, increased pleural and liver attenuation are not typically seen as a result of heart failure with reduced ejection fraction, making this diagnosis less likely.

Bacterial pneumonia typically presents with cough, fever, and purulent sputum production.⁹ Further evaluation usually reveals decreased breath sounds, dullness to percussion, and leukocytosis.¹⁰ Chest CT in bacterial pneumonia commonly shows a focal area of consolidation, which was not seen in our patient.¹¹

Idiopathic pulmonary fibrosis usually presents with slowly progressive dyspnea and nonproductive cough.¹² Physical examination usually reveals fine crackles and occasionally end-inspiratory “squeaks” if traction bronchiectasis is present.¹² The diagnosis of idiopathic pulmonary fibrosis requires chest CT findings compatible with it (ie, basal fibrosis, reticular abnormalities, and honeycombing). However, it remains a diagnosis of exclusion and requires ruling out conditions known to cause pulmonary fibrosis such as hypersensitivity pneumonitis, connective tissue disease, and certain medications.¹²

Although idiopathic pulmonary fibrosis remained in the differential diagnosis, our patient remained on amiodarone, a known cause of pulmonary fibrosis.¹³ Similarly, the high-attenuation pleural lesions likely represented organizing pneumonia, which is more common in amiodarone pulmonary toxicity. And the ground-glass opacities made idiopathic pulmonary fibrosis unlikely, although they may be seen in an acute exacerbation of this disease.¹⁴ Thus, a diagnosis of idiopathic pulmonary fibrosis could not be made definitively.

Amiodarone pulmonary toxicity most commonly presents with acute to subacute cough and progressive dyspnea.¹³ Physical findings are similar to those in idiopathic pulmonary fibrosis and commonly include bibasilar crackles. Chest CT shows diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation of multiple organs, including the lungs, liver, and spleen.¹⁴ Bronchoalveolar lavage findings of lipid-laden macrophages suggest but do not definitively diagnose amiodarone pulmonary toxicity.¹⁵ And patients with acute amiodarone pulmonary toxicity may present with pigment-laden macrophages on bronchoalveolar lavage, as in our patient.¹⁶

Exclusion of hypersensitivity pneumonitis, connective tissue disease, and infection made our patient’s progressive dyspnea and chest CT findings of ground-glass opacities, fibrosis, and increased pulmonary and liver attenuation most consistent with amiodarone pulmonary toxicity.

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

• Surgical lung biopsy
• Stop amiodarone and start supportive influenza management
• Stop amiodarone and start dronedarone
• Start an intravenous corticosteroid

Surgical lung biopsy is typically not required for diagnosis in patients with suspected amiodarone pulmonary toxicity. In addition, acute respiratory distress syndrome has been documented in patients who have undergone surgical biopsy for suspected amiodarone pulmonary toxicity.¹⁷

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Stopping amiodarone and starting supportive influenza management are the best next steps, as our patient’s fevers, cough, dyspnea, and laboratory test results were consistent with influenza.¹⁸ Moreover, CT findings of ground-glass opacities and reticular abnormalities can be seen in influenza.¹⁹

However, concomitant amiodarone pulmonary toxicity could not be ruled out, as CT showed increased lung and liver attenuation and fibrosis that could not be explained by influenza. And the elevation in aminotransferase levels more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity. However, definitive diagnosis would require exclusion of other causes such as congestive hepatopathy, in some cases with liver biopsy.¹³

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

Dronedarone is an antiarrhythmic drug structurally and functionally similar to amiodarone. There are far fewer reports of pulmonary toxicity with dronedarone than with amiodarone.²⁰ However, lack of data on dronedarone in amiodarone pulmonary toxicity, increased rates of hospitalization and death associated with dronedarone in patients like ours with advanced heart failure, and our patient’s previously implanted cardioverter-defibrillator for recurrent ventricular tachycardia all made dronedarone an undesirable alternative to amiodarone.²¹

Corticosteroids are useful in the treatment of amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis.¹³ Our patient’s hypoxia and dyspnea were thought to be due in part to her acute influenza infection, and therefore corticosteroids were not used at the outset.

However, concomitant amiodarone pulmonary toxicity could not be excluded, and the elevation in aminotransferases of more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity—though congestive hepatopathy remained in the differential diagnosis. Therefore, supportive therapy for influenza was instituted, and amiodarone was withheld. Her condition subsequently improved, and she was discharged.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

• FEV₁ 0.69 L (56% of predicted)
• FVC 1.08 L (64% of predicted)

• 

  FEV₁/FVC ratio 64%
• DLCO 2.20 mL/min/mm Hg (12% of predicted).

Aminotransferase levels had also normalized. Repeat chest CT showed persistent bibasilar interstitial fibrotic changes, enlarging bilateral pleural effusions, and persistent peripheral ground-glass opacities (Figure 2).

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

• No further management, continue to hold amiodarone
• Corticosteroids
• Repeat bronchoalveolar lavage
• Intravenous antibiotics

No further management of amiodarone pulmonary toxicity would be appropriate if our patient did not have a high burden of symptoms. However, when patients with amiodarone pulmonary toxicity present with hypoxia and dyspnea, corticosteroids should be started.¹³ Our patient remained symptomatic after discontinuation of amiodarone and resolution of her influenza infection, and CT showed persistent signs of amiodarone pulmonary toxicity, which required further management.

Corticosteroids are useful in treating amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis. Our patient’s persistent ground-glass opacities, fibrotic changes, and increased attenuation in multiple organs on CT, coupled with a confirmed reduction in FVC of greater than 15% and reduction in DLCO of greater than 20% after recovery from influenza, were most consistent with persistent amiodarone pulmonary toxicity.¹³

Although our patient’s amiodarone had been discontinued, the long half-life of the drug (45 days) allowed pulmonary toxicity to progress even after the drug was discontinued.²² Because our patient continued to have hypoxia and dyspnea on exertion, the most appropriate next step in management (in addition to managing her pleural effusions) was to start corticosteroids.

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

Bronchoalveolar lavage is typically used in suspected cases of amiodarone pulmonary toxicity only to rule out an alternative diagnosis such as infection. Lipid-laden macrophages may be seen in the fluid. However, lipid-laden macrophages are not diagnostic of amiodarone pulmonary toxicity, as this finding may also be seen in patients taking amiodarone who do not develop pulmonary toxicity.¹⁵ Other findings on bronchoalveolar lavage in amiodarone pulmonary toxicity are nonspecific and are not diagnostically useful.¹³

Intravenous antibiotics are appropriate if bacterial pneumonia is suspected. However, bacterial pneumonia typically presents with cough, fever, purulent sputum production, and focal consolidation on chest imaging.⁹ Our patient’s CT findings of persistent peripheral ground-glass opacities and lack of cough, fever, or purulent sputum production were not consistent with bacterial pneumonia, and therefore intravenous antibiotics were not indicated.

CASE CONCLUSION

Given our patient’s persistent dyspnea, hypoxia, and chest CT findings consistent with amiodarone pulmonary toxicity, it was recommended that she start corticosteroids. However, before starting therapy, she suffered a femoral fracture that required surgical intervention. Around the time of the procedure, she had an ST-segment elevation myocardial infarction requiring vasopressor support and mechanical ventilation. At that time, the patient and family decided to pursue comfort measures, and she died peacefully.

MORE ABOUT AMIODARONE PULMONARY TOXICITY

Pulmonary toxicity is a well-described consequence of amiodarone therapy.²³ Amiodarone carries a 2% risk of pulmonary toxicity.²⁴ Although higher doses are more likely to cause pulmonary toxicity, lower doses also have been implicated.^22,24 Preexisting pulmonary disease may predispose patients taking amiodarone to pulmonary toxicity; however, this is not uniformly seen.²⁵

Mortality rates as high as 10% from amiodarone pulmonary toxicity have been reported. Thus, diligent surveillance for pulmonary toxicity with pulmonary function tests in patients taking amiodarone is mandatory. In particular, a reduction in FVC of greater than 15% or in DLCO of greater than 20% from baseline may be seen in amiodarone pulmonary toxicity.²⁶

Amiodarone pulmonary toxicity can present at any time after the start of therapy, but it occurs most often after 6 to 12 months.¹³ Patients typically experience insidious dyspnea; however, presentation with acute to subacute cough and progressive dyspnea can occur, especially with high concentrations of supplemental oxygen with or without mechanical ventilation.^12,27 Findings on physical examination include bibasilar crackles. CT chest findings include diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation in multiple organs, including the lung, liver, and spleen.¹⁴

The diagnosis of amiodarone pulmonary toxicity requires ruling out hypersensitivity pneumonitis, connective tissue disease, heart failure, and infection. Surgical biopsy and bronchoalveolar lavage are not commonly used to establish the diagnosis of amiodarone pulmonary toxicity, as surgical biopsy increases the risk of acute respiratory distress syndrome, and the results of bronchoalveolar lavage are usually nonspecific.^13,15

Initial treatment involves discontinuing the amiodarone once the diagnosis is suspected. If patients have worsening hypoxia or dyspnea at the time of diagnosis, corticosteroids can be used. Prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering of corticosteroids should occur slowly and may take several months.

An 87-year-old woman was brought to the intensive care unit with worsening shortness of breath on exertion, fatigue, orthopnea, paroxysmal nocturnal dyspnea, lower extremity swelling, subjective fever, productive cough, and rhinorrhea over the last week. She reported no chest pain, lightheadedness, or palpitations. Her medical history included the following:

• Coronary artery disease requiring coronary artery bypass grafting
• Ischemic cardiomyopathy
• Severe mitral regurgitation
• Moderate tricuspid regurgitation
• Pulmonary hypertension
• Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
• Hypothyroidism requiring levothyroxine
• Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
• Long-standing essential thrombocythemia treated with hydroxyurea.

Before admission, she had been reliably taking guideline-directed heart failure therapy as well as amiodarone for her recurrent ventricular tachycardia. Her levothyroxine had recently been increased as well.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

• Acute decompensated heart failure
• Pulmonary embolism
• Exacerbation of asthma
• Exacerbation of chronic obstructive pulmonary disease (COPD)

Heart failure is a clinical diagnosis based on careful history-taking and physical examination. Major criteria include paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary crackles, a third heart sound, cardiomegaly, pulmonary edema, and weight loss of more than 4.5 kg with diuretic therapy.¹ N-terminal pro-B-type natriuretic peptide (NT-proBNP) is also an effective marker of acute decompensated heart failure in the proper clinical setting.²

Our patient’s elevated jugular venous pressure, bibasilar crackles, lower extremity edema, chest radiography findings consistent with pulmonary edema, markedly elevated NT-proBNP, history of orthopnea, paroxysmal nocturnal dyspnea, and dyspnea on exertion were most consistent with acute decompensated heart failure. Her cough and subjective fevers were thought to be due to an upper respiratory tract viral infection.

Pulmonary embolism causes pleuritic chest pain, dyspnea, and, occasionally, elevated troponin. The most common feature on electrocardiography is sinus tachycardia; nonspecific ST-segment and T-wave changes may also be seen.³

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

Although our patient presented with cough and dyspnea, she had no history of COPD and her other signs and symptoms (elevated jugular venous pressure, elevated NT-proBNP, and peripheral edema) could not be explained by COPD exacerbation.

Echocardiography revealed severe left ventricular enlargement, an ejection fraction of 20% (which was near her baseline value), diffuse regional wall-motion abnormalities, severe mitral regurgitation, and moderate tricuspid regurgitation consistent with an exacerbation of heart failure.

We considered the possibility that her heart failure symptoms might be due to precipitous up-titration of her levothyroxine dose, given her borderline-elevated free thyroxine (T₄) and increase in cardiac index (currently 4.45 L/min/m², previously 2.20 L/min/m² by the left ventricular outflow tract velocity time integral method). However, given her reduced ejection fraction, this clinical presentation most likely represented an acute exacerbation of her chronic heart failure. Her subjective fevers were thought to be due to a viral infection of the upper respiratory tract. The macrocytic anemia and thrombocytopenia were thought to be a side effect of her long-standing treatment with hydroxyurea for essential thrombocythemia, although amiodarone has also been associated with cytopenia.⁸

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

Further testing for connective tissue disease and hypersensitivity pneumonitis was also done, and the results were negative. To exclude an atypical infection, bronchoalveolar lavage was performed; preliminary microbial testing was negative, and the white blood cell count in the lavage fluid was 90% macrophages (pigment-laden), 7% neutrophils, and 3% lymphocytes.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

• Heart failure with reduced ejection fraction
• Bacterial pneumonia
• Idiopathic pulmonary fibrosis
• Amiodarone pulmonary toxicity

Heart failure with reduced ejection fraction can cause ground-glass opacities on CT due to increased pulmonary edema. Although our patient initially presented with acute decompensation of heart failure with reduced ejection fraction decompensation, she had returned to euvolemia after aggressive diuresis. Moreover, increased pleural and liver attenuation are not typically seen as a result of heart failure with reduced ejection fraction, making this diagnosis less likely.

Bacterial pneumonia typically presents with cough, fever, and purulent sputum production.⁹ Further evaluation usually reveals decreased breath sounds, dullness to percussion, and leukocytosis.¹⁰ Chest CT in bacterial pneumonia commonly shows a focal area of consolidation, which was not seen in our patient.¹¹

Idiopathic pulmonary fibrosis usually presents with slowly progressive dyspnea and nonproductive cough.¹² Physical examination usually reveals fine crackles and occasionally end-inspiratory “squeaks” if traction bronchiectasis is present.¹² The diagnosis of idiopathic pulmonary fibrosis requires chest CT findings compatible with it (ie, basal fibrosis, reticular abnormalities, and honeycombing). However, it remains a diagnosis of exclusion and requires ruling out conditions known to cause pulmonary fibrosis such as hypersensitivity pneumonitis, connective tissue disease, and certain medications.¹²

Although idiopathic pulmonary fibrosis remained in the differential diagnosis, our patient remained on amiodarone, a known cause of pulmonary fibrosis.¹³ Similarly, the high-attenuation pleural lesions likely represented organizing pneumonia, which is more common in amiodarone pulmonary toxicity. And the ground-glass opacities made idiopathic pulmonary fibrosis unlikely, although they may be seen in an acute exacerbation of this disease.¹⁴ Thus, a diagnosis of idiopathic pulmonary fibrosis could not be made definitively.

Amiodarone pulmonary toxicity most commonly presents with acute to subacute cough and progressive dyspnea.¹³ Physical findings are similar to those in idiopathic pulmonary fibrosis and commonly include bibasilar crackles. Chest CT shows diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation of multiple organs, including the lungs, liver, and spleen.¹⁴ Bronchoalveolar lavage findings of lipid-laden macrophages suggest but do not definitively diagnose amiodarone pulmonary toxicity.¹⁵ And patients with acute amiodarone pulmonary toxicity may present with pigment-laden macrophages on bronchoalveolar lavage, as in our patient.¹⁶

Exclusion of hypersensitivity pneumonitis, connective tissue disease, and infection made our patient’s progressive dyspnea and chest CT findings of ground-glass opacities, fibrosis, and increased pulmonary and liver attenuation most consistent with amiodarone pulmonary toxicity.

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

• Surgical lung biopsy
• Stop amiodarone and start supportive influenza management
• Stop amiodarone and start dronedarone
• Start an intravenous corticosteroid

Surgical lung biopsy is typically not required for diagnosis in patients with suspected amiodarone pulmonary toxicity. In addition, acute respiratory distress syndrome has been documented in patients who have undergone surgical biopsy for suspected amiodarone pulmonary toxicity.¹⁷

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Stopping amiodarone and starting supportive influenza management are the best next steps, as our patient’s fevers, cough, dyspnea, and laboratory test results were consistent with influenza.¹⁸ Moreover, CT findings of ground-glass opacities and reticular abnormalities can be seen in influenza.¹⁹

However, concomitant amiodarone pulmonary toxicity could not be ruled out, as CT showed increased lung and liver attenuation and fibrosis that could not be explained by influenza. And the elevation in aminotransferase levels more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity. However, definitive diagnosis would require exclusion of other causes such as congestive hepatopathy, in some cases with liver biopsy.¹³

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

Dronedarone is an antiarrhythmic drug structurally and functionally similar to amiodarone. There are far fewer reports of pulmonary toxicity with dronedarone than with amiodarone.²⁰ However, lack of data on dronedarone in amiodarone pulmonary toxicity, increased rates of hospitalization and death associated with dronedarone in patients like ours with advanced heart failure, and our patient’s previously implanted cardioverter-defibrillator for recurrent ventricular tachycardia all made dronedarone an undesirable alternative to amiodarone.²¹

Corticosteroids are useful in the treatment of amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis.¹³ Our patient’s hypoxia and dyspnea were thought to be due in part to her acute influenza infection, and therefore corticosteroids were not used at the outset.

However, concomitant amiodarone pulmonary toxicity could not be excluded, and the elevation in aminotransferases of more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity—though congestive hepatopathy remained in the differential diagnosis. Therefore, supportive therapy for influenza was instituted, and amiodarone was withheld. Her condition subsequently improved, and she was discharged.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

• FEV₁ 0.69 L (56% of predicted)
• FVC 1.08 L (64% of predicted)

• 

  FEV₁/FVC ratio 64%
• DLCO 2.20 mL/min/mm Hg (12% of predicted).

Aminotransferase levels had also normalized. Repeat chest CT showed persistent bibasilar interstitial fibrotic changes, enlarging bilateral pleural effusions, and persistent peripheral ground-glass opacities (Figure 2).

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

• No further management, continue to hold amiodarone
• Corticosteroids
• Repeat bronchoalveolar lavage
• Intravenous antibiotics

No further management of amiodarone pulmonary toxicity would be appropriate if our patient did not have a high burden of symptoms. However, when patients with amiodarone pulmonary toxicity present with hypoxia and dyspnea, corticosteroids should be started.¹³ Our patient remained symptomatic after discontinuation of amiodarone and resolution of her influenza infection, and CT showed persistent signs of amiodarone pulmonary toxicity, which required further management.

Corticosteroids are useful in treating amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis. Our patient’s persistent ground-glass opacities, fibrotic changes, and increased attenuation in multiple organs on CT, coupled with a confirmed reduction in FVC of greater than 15% and reduction in DLCO of greater than 20% after recovery from influenza, were most consistent with persistent amiodarone pulmonary toxicity.¹³

Although our patient’s amiodarone had been discontinued, the long half-life of the drug (45 days) allowed pulmonary toxicity to progress even after the drug was discontinued.²² Because our patient continued to have hypoxia and dyspnea on exertion, the most appropriate next step in management (in addition to managing her pleural effusions) was to start corticosteroids.

For amiodarone pulmonary toxicity, prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering should be slow and may take several months.

Bronchoalveolar lavage is typically used in suspected cases of amiodarone pulmonary toxicity only to rule out an alternative diagnosis such as infection. Lipid-laden macrophages may be seen in the fluid. However, lipid-laden macrophages are not diagnostic of amiodarone pulmonary toxicity, as this finding may also be seen in patients taking amiodarone who do not develop pulmonary toxicity.¹⁵ Other findings on bronchoalveolar lavage in amiodarone pulmonary toxicity are nonspecific and are not diagnostically useful.¹³

Intravenous antibiotics are appropriate if bacterial pneumonia is suspected. However, bacterial pneumonia typically presents with cough, fever, purulent sputum production, and focal consolidation on chest imaging.⁹ Our patient’s CT findings of persistent peripheral ground-glass opacities and lack of cough, fever, or purulent sputum production were not consistent with bacterial pneumonia, and therefore intravenous antibiotics were not indicated.

CASE CONCLUSION

Given our patient’s persistent dyspnea, hypoxia, and chest CT findings consistent with amiodarone pulmonary toxicity, it was recommended that she start corticosteroids. However, before starting therapy, she suffered a femoral fracture that required surgical intervention. Around the time of the procedure, she had an ST-segment elevation myocardial infarction requiring vasopressor support and mechanical ventilation. At that time, the patient and family decided to pursue comfort measures, and she died peacefully.

MORE ABOUT AMIODARONE PULMONARY TOXICITY

Pulmonary toxicity is a well-described consequence of amiodarone therapy.²³ Amiodarone carries a 2% risk of pulmonary toxicity.²⁴ Although higher doses are more likely to cause pulmonary toxicity, lower doses also have been implicated.^22,24 Preexisting pulmonary disease may predispose patients taking amiodarone to pulmonary toxicity; however, this is not uniformly seen.²⁵

Mortality rates as high as 10% from amiodarone pulmonary toxicity have been reported. Thus, diligent surveillance for pulmonary toxicity with pulmonary function tests in patients taking amiodarone is mandatory. In particular, a reduction in FVC of greater than 15% or in DLCO of greater than 20% from baseline may be seen in amiodarone pulmonary toxicity.²⁶

Amiodarone pulmonary toxicity can present at any time after the start of therapy, but it occurs most often after 6 to 12 months.¹³ Patients typically experience insidious dyspnea; however, presentation with acute to subacute cough and progressive dyspnea can occur, especially with high concentrations of supplemental oxygen with or without mechanical ventilation.^12,27 Findings on physical examination include bibasilar crackles. CT chest findings include diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation in multiple organs, including the lung, liver, and spleen.¹⁴

The diagnosis of amiodarone pulmonary toxicity requires ruling out hypersensitivity pneumonitis, connective tissue disease, heart failure, and infection. Surgical biopsy and bronchoalveolar lavage are not commonly used to establish the diagnosis of amiodarone pulmonary toxicity, as surgical biopsy increases the risk of acute respiratory distress syndrome, and the results of bronchoalveolar lavage are usually nonspecific.^13,15

Initial treatment involves discontinuing the amiodarone once the diagnosis is suspected. If patients have worsening hypoxia or dyspnea at the time of diagnosis, corticosteroids can be used. Prednisone is typically started at 40 to 60 mg daily and can result in rapid improvement in symptoms.¹³ Tapering of corticosteroids should occur slowly and may take several months.

An 87-year-old woman was brought to the intensive care unit with worsening shortness of breath on exertion, fatigue, orthopnea, paroxysmal nocturnal dyspnea, lower extremity swelling, subjective fever, productive cough, and rhinorrhea over the last week. She reported no chest pain, lightheadedness, or palpitations. Her medical history included the following:

• Coronary artery disease requiring coronary artery bypass grafting
• Ischemic cardiomyopathy
• Severe mitral regurgitation
• Moderate tricuspid regurgitation
• Pulmonary hypertension
• Cardiac arrest with recurrent ventricular tachycardia requiring an implanted cardioverter-defibrillator and amiodarone therapy
• Hypothyroidism requiring levothyroxine
• Asthma with a moderate obstructive pattern: forced expiratory volume in 1 second (FEV₁) 60% of predicted, forced vital capacity (FVC) 2.06 L, FEV₁/FVC 54%, diffusing capacity for carbon monoxide (DLCO) 72% of predicted with positive bronchodilator response
• Long-standing essential thrombocythemia treated with hydroxyurea.

Before admission, she had been reliably taking guideline-directed heart failure therapy as well as amiodarone for her recurrent ventricular tachycardia. Her levothyroxine had recently been increased as well.

Initial laboratory evaluation revealed abnormal values (Table 1).

Electrocardiography showed sinus rhythm and an old left bundle branch block.

Chest radiography showed cardiomegaly, bilateral pleural effusions, and pulmonary edema.

WHAT IS THE CAUSE OF HER SYMPTOMS?

1. Based on the available information, which of the following is the most likely cause of this patient’s clinical presentation?

• Acute decompensated heart failure
• Pulmonary embolism
• Exacerbation of asthma
• Exacerbation of chronic obstructive pulmonary disease (COPD)

Heart failure is a clinical diagnosis based on careful history-taking and physical examination. Major criteria include paroxysmal nocturnal dyspnea, orthopnea, elevated jugular venous pressure, pulmonary crackles, a third heart sound, cardiomegaly, pulmonary edema, and weight loss of more than 4.5 kg with diuretic therapy.¹ N-terminal pro-B-type natriuretic peptide (NT-proBNP) is also an effective marker of acute decompensated heart failure in the proper clinical setting.²

Our patient’s elevated jugular venous pressure, bibasilar crackles, lower extremity edema, chest radiography findings consistent with pulmonary edema, markedly elevated NT-proBNP, history of orthopnea, paroxysmal nocturnal dyspnea, and dyspnea on exertion were most consistent with acute decompensated heart failure. Her cough and subjective fevers were thought to be due to an upper respiratory tract viral infection.

Pulmonary embolism causes pleuritic chest pain, dyspnea, and, occasionally, elevated troponin. The most common feature on electrocardiography is sinus tachycardia; nonspecific ST-segment and T-wave changes may also be seen.³

Although pulmonary embolism remained in the differential diagnosis, our patient’s lack of typical features of pulmonary embolism made this less likely.

Asthma is characterized by recurrent airflow obstruction and bronchial hyperresponsiveness.⁴ Asthma exacerbations present with wheezing, tachypnea, tachycardia, and pulsus paradoxus.⁵

Despite her previous asthma diagnosis, our patient’s lack of typical features of asthma exacerbation made this diagnosis unlikely.

COPD exacerbations present with increased dyspnea, cough, sputum production, wheezing, lung resonance to percussion, and distant heart sounds, and are characterized by airflow obstruction.^6,7

Although our patient presented with cough and dyspnea, she had no history of COPD and her other signs and symptoms (elevated jugular venous pressure, elevated NT-proBNP, and peripheral edema) could not be explained by COPD exacerbation.

Echocardiography revealed severe left ventricular enlargement, an ejection fraction of 20% (which was near her baseline value), diffuse regional wall-motion abnormalities, severe mitral regurgitation, and moderate tricuspid regurgitation consistent with an exacerbation of heart failure.

We considered the possibility that her heart failure symptoms might be due to precipitous up-titration of her levothyroxine dose, given her borderline-elevated free thyroxine (T₄) and increase in cardiac index (currently 4.45 L/min/m², previously 2.20 L/min/m² by the left ventricular outflow tract velocity time integral method). However, given her reduced ejection fraction, this clinical presentation most likely represented an acute exacerbation of her chronic heart failure. Her subjective fevers were thought to be due to a viral infection of the upper respiratory tract. The macrocytic anemia and thrombocytopenia were thought to be a side effect of her long-standing treatment with hydroxyurea for essential thrombocythemia, although amiodarone has also been associated with cytopenia.⁸

Treatment was started with intravenous diuretics and positive pressure ventilation with oxygen supplementation. Her levothyroxine dose was reduced, and her hydroxyurea was stopped.

Further testing for connective tissue disease and hypersensitivity pneumonitis was also done, and the results were negative. To exclude an atypical infection, bronchoalveolar lavage was performed; preliminary microbial testing was negative, and the white blood cell count in the lavage fluid was 90% macrophages (pigment-laden), 7% neutrophils, and 3% lymphocytes.

WHAT IS THE CAUSE OF HER PERSISTENT PULMONARY FINDINGS?

2. Given the CT findings and laboratory results, what is the most likely cause of our patient’s persistent crackles and hypoxia?

• Heart failure with reduced ejection fraction
• Bacterial pneumonia
• Idiopathic pulmonary fibrosis
• Amiodarone pulmonary toxicity

Heart failure with reduced ejection fraction can cause ground-glass opacities on CT due to increased pulmonary edema. Although our patient initially presented with acute decompensation of heart failure with reduced ejection fraction decompensation, she had returned to euvolemia after aggressive diuresis. Moreover, increased pleural and liver attenuation are not typically seen as a result of heart failure with reduced ejection fraction, making this diagnosis less likely.

Bacterial pneumonia typically presents with cough, fever, and purulent sputum production.⁹ Further evaluation usually reveals decreased breath sounds, dullness to percussion, and leukocytosis.¹⁰ Chest CT in bacterial pneumonia commonly shows a focal area of consolidation, which was not seen in our patient.¹¹

Idiopathic pulmonary fibrosis usually presents with slowly progressive dyspnea and nonproductive cough.¹² Physical examination usually reveals fine crackles and occasionally end-inspiratory “squeaks” if traction bronchiectasis is present.¹² The diagnosis of idiopathic pulmonary fibrosis requires chest CT findings compatible with it (ie, basal fibrosis, reticular abnormalities, and honeycombing). However, it remains a diagnosis of exclusion and requires ruling out conditions known to cause pulmonary fibrosis such as hypersensitivity pneumonitis, connective tissue disease, and certain medications.¹²

Although idiopathic pulmonary fibrosis remained in the differential diagnosis, our patient remained on amiodarone, a known cause of pulmonary fibrosis.¹³ Similarly, the high-attenuation pleural lesions likely represented organizing pneumonia, which is more common in amiodarone pulmonary toxicity. And the ground-glass opacities made idiopathic pulmonary fibrosis unlikely, although they may be seen in an acute exacerbation of this disease.¹⁴ Thus, a diagnosis of idiopathic pulmonary fibrosis could not be made definitively.

Amiodarone pulmonary toxicity most commonly presents with acute to subacute cough and progressive dyspnea.¹³ Physical findings are similar to those in idiopathic pulmonary fibrosis and commonly include bibasilar crackles. Chest CT shows diffuse ground-glass opacities, reticular abnormalities, fibrosis, and increased attenuation of multiple organs, including the lungs, liver, and spleen.¹⁴ Bronchoalveolar lavage findings of lipid-laden macrophages suggest but do not definitively diagnose amiodarone pulmonary toxicity.¹⁵ And patients with acute amiodarone pulmonary toxicity may present with pigment-laden macrophages on bronchoalveolar lavage, as in our patient.¹⁶

Exclusion of hypersensitivity pneumonitis, connective tissue disease, and infection made our patient’s progressive dyspnea and chest CT findings of ground-glass opacities, fibrosis, and increased pulmonary and liver attenuation most consistent with amiodarone pulmonary toxicity.

Amiodarone was therefore discontinued. However, the test result of her lavage fluid for influenza A by polymerase chain reaction came back positive a few hours later.

3. Given the positive influenza A polymerase chain reaction test, which of the following is the best next step in this patient’s management?

• Surgical lung biopsy
• Stop amiodarone and start supportive influenza management
• Stop amiodarone and start dronedarone
• Start an intravenous corticosteroid

Surgical lung biopsy is typically not required for diagnosis in patients with suspected amiodarone pulmonary toxicity. In addition, acute respiratory distress syndrome has been documented in patients who have undergone surgical biopsy for suspected amiodarone pulmonary toxicity.¹⁷

Thus, surgical biopsy is typically only done in cases of persistent symptoms despite withdrawal of amiodarone and initiation of steroid therapy.

Stopping amiodarone and starting supportive influenza management are the best next steps, as our patient’s fevers, cough, dyspnea, and laboratory test results were consistent with influenza.¹⁸ Moreover, CT findings of ground-glass opacities and reticular abnormalities can be seen in influenza.¹⁹

However, concomitant amiodarone pulmonary toxicity could not be ruled out, as CT showed increased lung and liver attenuation and fibrosis that could not be explained by influenza. And the elevation in aminotransferase levels more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity. However, definitive diagnosis would require exclusion of other causes such as congestive hepatopathy, in some cases with liver biopsy.¹³

Our patient’s persistent hypoxia was thought to be due in part to influenza, and thus the best next step in management was to stop amiodarone and provide supportive care for influenza.

Dronedarone is an antiarrhythmic drug structurally and functionally similar to amiodarone. There are far fewer reports of pulmonary toxicity with dronedarone than with amiodarone.²⁰ However, lack of data on dronedarone in amiodarone pulmonary toxicity, increased rates of hospitalization and death associated with dronedarone in patients like ours with advanced heart failure, and our patient’s previously implanted cardioverter-defibrillator for recurrent ventricular tachycardia all made dronedarone an undesirable alternative to amiodarone.²¹

Corticosteroids are useful in the treatment of amiodarone pulmonary toxicity when hypoxia and dyspnea are present at diagnosis.¹³ Our patient’s hypoxia and dyspnea were thought to be due in part to her acute influenza infection, and therefore corticosteroids were not used at the outset.

However, concomitant amiodarone pulmonary toxicity could not be excluded, and the elevation in aminotransferases of more than 2 times the upper limit of normal and CT findings of increased liver attenuation suggested amiodarone hepatotoxicity—though congestive hepatopathy remained in the differential diagnosis. Therefore, supportive therapy for influenza was instituted, and amiodarone was withheld. Her condition subsequently improved, and she was discharged.

FOLLOW-UP 1 MONTH LATER

At a follow-up visit 1 month later, our patient continued to have dyspnea and hypoxia. She did not have signs or symptoms consistent with decompensated heart failure.

Pulmonary function testing revealed the following values:

• FEV₁ 0.69 L (56% of predicted)
• FVC 1.08 L (64% of predicted)

• 

  FEV₁/FVC ratio 64%
• DLCO 2.20 mL/min/mm Hg (12% of predicted).

Aminotransferase levels had also normalized. Repeat chest CT showed persistent bibasilar interstitial fibrotic changes, enlarging bilateral pleural effusions, and persistent peripheral ground-glass opacities (Figure 2).

4. Given the chest CT findings, which of the following is the most appropriate treatment strategy for this patient?

• No further management, continue to hold amiodarone
• Corticosteroids
• Repeat bronchoalveolar lavage
• Intravenous antibiotics

No further management of amiodarone pulmonary toxicity would be appropriate if our patient did not have a high burden of symptoms. However, when patients with amiodarone pulmonary toxicity present with hypoxia and dyspnea, corticosteroids should be started.¹³ Our patient remained symptomatic after discontinuation of amiodarone and resolution of her influenza infection, and CT showed persistent signs of amiodarone pulmonary toxicity, which required further management.