William Rodriguez-Cintrón, MD

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

 

The early negative bronchoscopy lowered the possibility of an infection as the etiology of the clinical presentation and narrowed the hyperferritinemia differential diagnosis. Hyperferritinemia has a sensitivity and specificity of > 90% for diagnosis when above 10,000 ng/dL in the pediatric population.⁷ This is not the case in adults. Hyperferritinemia is a marker of different inflammatory responses, such as histoplasmosis infection, malignancy, or iron overload rather than an isolated diagnostic tool for HLH.⁸ It has been reported that CD25 levels less than the diagnostic threshold of 2400 U/mL have a 100% sensitivity for the diagnosis and therefore can rule out the diagnosis. When this is taken into consideration, it can be concluded that CD25 level is a better diagnostic tool when compared with ferritin, but its main limitation is its lack of widespread availability.⁹ Still, there is a limited number of pathologies that are associated with marked hyperferritinemia, specifically using thresholds of more than 6000 ng/dL.¹⁰ Taking into consideration the high mortality of untreated HLH, isolated hyperferritinemia still warrants HLH workup to aggressively pursue the diagnosis and improve outcomes.

The goal of therapy in HLH is prompt inactivation of the dysregulated inflammation with aggressive immunosuppression. In our deteriorating patient, the treatment was started with only 4 of the 8 HLH-2004 diagnostic criteria being met. As per the 2018 Histiocyte Society consensus statement, the decision to start the HLH-94 treatment relies on not only the HLH-2004 diagnostic criteria, but also the patient’s clinical evolution.¹¹ In 1994 the Histiocyte Society also published a treatment protocol termed HLH-94. A Korean retrospective study demonstrated that this protocol led to a 5-year survival rate of 60 to 80% depending on the HLH trigger and response to initial treatment.¹² The protocol consists of etoposide at 150 mg/m², 2 weekly doses in the first 2 weeks and then 1 dose weekly for the next 6 weeks. Dexamethasone is the steroid of choice as it readily crosses the blood-brain barrier. Its dosage consists of 10 mg/m² for the first 2 weeks and then it is halved every 2 weeks until the eighth week of treatment. A slow taper follows to avoid adrenal insufficiency. Once 8 weeks of treatment have been completed, cyclosporine is added to a goal trough of 200 mcg/dL. If there is central nervous system (CNS) involvement, early aggressive treatment with intrathecal methotrexate is indicated if no improvement is noted during initial therapy.¹¹

In 2004 the Histiocyte Society restructured the HLH-94 treatment protocol with the aim of presenting a more aggressive treatment strategy. The protocol added cyclosporine to the initial induction therapy, rather than later in the ninth week as HLH-94. Neither the use of cyclosporine nor the HLH-2004 have been demonstrated to be superior to the use of etoposide and dexamethasone alone or in the HLH-94 protocol, respectively.¹³ Cyclosporine is associated with adverse effects (AEs) and may have many contraindications in the acute phase of the disease. Therefore, the HLH-94 protocol is still the recommended regimen.¹¹

To assess adequate clinical response, several clinical and laboratory parameters are followed. Clinically, resolution of fever, improvement in hepatosplenomegaly, lymphadenopathy, and mental status can be useful. Laboratories can be used to assess improvement from organ specific damage such as hepatic involvement or cytopenia. The limitation of these diagnostic studies is that they could falsely suggest an inadequate response to treatment due to concomitant infection or medication AEs. Other markers such as ferritin levels, CD25, and NK cell activity levels are more specific to HLH. Out of them, a decreasing ferritin level has the needed specificity and widespread availability for repeated assessment. On the other hand, both CD25 and NK cell activity are readily available only in specialized centers. An initial high ferritin level is a marker for a poor prognosis, and the rate of decline correlates with mortality. Studies have demonstrated that persistently elevated ferritin levels after treatment initiation are associated with worse outcomes.^14,15

Several salvage treatments have been identified in recalcitrant or relapsing disease. In general, chemotherapy needs to be intensified, either by returning to the initial high dosage if recurrence occurs in the weaning phase of treatment or adding other agents if no response was initially achieved. Emapalumab, an interferon γ antibody, was approved by the US Food and Drug Administration for the treatment of intractable HLH after it demonstrated that when added to dexamethasone, it lead to treatment response in 17 out of 27 pediatric patients, with a relatively safe AE profile.¹⁶ The goal of intensifying chemotherapy is to have the patient tolerate allogenic stem cell transplant, which is clinically indicated in familial HLH, malignancy induced HLH, and recalcitrant cases. In patients who undergo hematopoietic cell transplantation (HCT) there is a tendency to increase survival to 66% at 5 years.¹²

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

 

The early negative bronchoscopy lowered the possibility of an infection as the etiology of the clinical presentation and narrowed the hyperferritinemia differential diagnosis. Hyperferritinemia has a sensitivity and specificity of > 90% for diagnosis when above 10,000 ng/dL in the pediatric population.⁷ This is not the case in adults. Hyperferritinemia is a marker of different inflammatory responses, such as histoplasmosis infection, malignancy, or iron overload rather than an isolated diagnostic tool for HLH.⁸ It has been reported that CD25 levels less than the diagnostic threshold of 2400 U/mL have a 100% sensitivity for the diagnosis and therefore can rule out the diagnosis. When this is taken into consideration, it can be concluded that CD25 level is a better diagnostic tool when compared with ferritin, but its main limitation is its lack of widespread availability.⁹ Still, there is a limited number of pathologies that are associated with marked hyperferritinemia, specifically using thresholds of more than 6000 ng/dL.¹⁰ Taking into consideration the high mortality of untreated HLH, isolated hyperferritinemia still warrants HLH workup to aggressively pursue the diagnosis and improve outcomes.

The goal of therapy in HLH is prompt inactivation of the dysregulated inflammation with aggressive immunosuppression. In our deteriorating patient, the treatment was started with only 4 of the 8 HLH-2004 diagnostic criteria being met. As per the 2018 Histiocyte Society consensus statement, the decision to start the HLH-94 treatment relies on not only the HLH-2004 diagnostic criteria, but also the patient’s clinical evolution.¹¹ In 1994 the Histiocyte Society also published a treatment protocol termed HLH-94. A Korean retrospective study demonstrated that this protocol led to a 5-year survival rate of 60 to 80% depending on the HLH trigger and response to initial treatment.¹² The protocol consists of etoposide at 150 mg/m², 2 weekly doses in the first 2 weeks and then 1 dose weekly for the next 6 weeks. Dexamethasone is the steroid of choice as it readily crosses the blood-brain barrier. Its dosage consists of 10 mg/m² for the first 2 weeks and then it is halved every 2 weeks until the eighth week of treatment. A slow taper follows to avoid adrenal insufficiency. Once 8 weeks of treatment have been completed, cyclosporine is added to a goal trough of 200 mcg/dL. If there is central nervous system (CNS) involvement, early aggressive treatment with intrathecal methotrexate is indicated if no improvement is noted during initial therapy.¹¹

In 2004 the Histiocyte Society restructured the HLH-94 treatment protocol with the aim of presenting a more aggressive treatment strategy. The protocol added cyclosporine to the initial induction therapy, rather than later in the ninth week as HLH-94. Neither the use of cyclosporine nor the HLH-2004 have been demonstrated to be superior to the use of etoposide and dexamethasone alone or in the HLH-94 protocol, respectively.¹³ Cyclosporine is associated with adverse effects (AEs) and may have many contraindications in the acute phase of the disease. Therefore, the HLH-94 protocol is still the recommended regimen.¹¹

To assess adequate clinical response, several clinical and laboratory parameters are followed. Clinically, resolution of fever, improvement in hepatosplenomegaly, lymphadenopathy, and mental status can be useful. Laboratories can be used to assess improvement from organ specific damage such as hepatic involvement or cytopenia. The limitation of these diagnostic studies is that they could falsely suggest an inadequate response to treatment due to concomitant infection or medication AEs. Other markers such as ferritin levels, CD25, and NK cell activity levels are more specific to HLH. Out of them, a decreasing ferritin level has the needed specificity and widespread availability for repeated assessment. On the other hand, both CD25 and NK cell activity are readily available only in specialized centers. An initial high ferritin level is a marker for a poor prognosis, and the rate of decline correlates with mortality. Studies have demonstrated that persistently elevated ferritin levels after treatment initiation are associated with worse outcomes.^14,15

Several salvage treatments have been identified in recalcitrant or relapsing disease. In general, chemotherapy needs to be intensified, either by returning to the initial high dosage if recurrence occurs in the weaning phase of treatment or adding other agents if no response was initially achieved. Emapalumab, an interferon γ antibody, was approved by the US Food and Drug Administration for the treatment of intractable HLH after it demonstrated that when added to dexamethasone, it lead to treatment response in 17 out of 27 pediatric patients, with a relatively safe AE profile.¹⁶ The goal of intensifying chemotherapy is to have the patient tolerate allogenic stem cell transplant, which is clinically indicated in familial HLH, malignancy induced HLH, and recalcitrant cases. In patients who undergo hematopoietic cell transplantation (HCT) there is a tendency to increase survival to 66% at 5 years.¹²

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and deadly disease in which unregulated proliferation of histiocytes and T-cell infiltration takes place. It is known as a pediatric disease in which gene defects result in impaired cytotoxic NK- and T-cell function. It has been associated with autosomal recessive inheritance pattern. Without therapy, survival for these patients with active familial HLH is approximately 2 months.

Recognition of the disease has increased over the years, and as a result the diagnosis of HLH in adults also has increased. An acquired form can be triggered by viruses like Epstein-Barr virus, influenza, HIV, lymphoid malignancies, rheumatologic disorders, or immunodeficiency disorders. Survival rates for untreated HLH have been reported at < 5%.¹ Despite early recognition and adequate treatment, HLH carries an overall mortality of 50% in the initial presentation, 90% die in the first 8 weeks of treatment due to uncontrolled disease.²

Case Presentation

A 56-year-old man with no active medical issues except for a remote history of non-Hodgkin lymphoma treated with chemotherapy and splenectomy in 1990 presented to the Veterans Affairs Caribbean Healthcare System in San Juan, Puerto Rico. He was admitted to the medicine ward due to community acquired pneumonia. Three days into admission his clinical status deteriorated, and the patient was transferred to the intensive care unit (ICU) due to acute respiratory failure and sepsis secondary to worsening pneumonia. Chest imaging demonstrated rapidly progressing diffuse bilateral infiltrates. Due to the severity of the chest imaging, a diagnostic bronchoscopy was performed.

The patient’s antibiotics regimen was empirically escalated to vancomycin 1500 mg IV every 12 hours and meropenem 2 g IV every 8 hours. Despite optimization of therapy, the patient did not show clinical signs of improvement. Febrile episodes persisted, pulmonary infiltrates and hypoxemia worsened, and the patient required a neuromuscular blockade. Since the bronchoscopy was nondiagnostic and deterioration persistent, the differential diagnosis was broadened. This led to the ordering of inflammatory markers. Laboratory testing showed ferritin levels > 16,000 ng/mL, pointing to HLH as a possible diagnosis. Further workup was remarkable for triglycerides of 1234 mg/dL and a fibrinogen of 0.77 g/L. In the setting of bicytopenia and persistent fever, HLH-94 regimen was started with dexamethasone 40 mg daily and etoposide 100 mg/m². CD25 levels of 154,701 pg/mL were demonstrated as well as a decreased immunoglobulin (Ig) G levels with absent IgM and IgA. Bone marrow biopsy was consistent with hemophagocytosis. The patient eventually was extubated and sent to the oncology ward to continue chemotherapy.

Discussion

A high clinical suspicion is warranted for rapid diagnosis and treatment as HLH evolves in most cases to multiorgan failure and death. The diagnostic criteria for HLH was developed by the Histiocyte Society in 1991 and then restructured in 2004.^3,4 In the first diagnostic tool developed in 1991, diagnosis was based on 5 criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). Three additional laboratory findings were also described as part of HLH diagnosis since 2004: low or absent NK-cell-activity, hyperferritinemia of > 500 ng/dL, and high-soluble interleukin-2-receptor levels (CD25) > 2400 U/mL. Overall, 5 of 8 criteria are needed for the HLH diagnosis.

Despite the common use of these diagnostic criteria, they were developed for the pediatric population but have not been validated for adult patients.⁵ For adult patients, the HScore was developed in 2014. It has 9 variables: 3 are based on clinical findings (known underlying immunosuppression, high temperature, and organomegaly; 5 are based on laboratory values (ferritin, serum glutamic oxaloacetic transaminase, cytopenia, triglycerides, and fibrinogen levels); the last variable uses cytologic findings in the bone marrow. In the initial study, probability of having HLH ranged from < 1% with an HScore of ≤ 90% to > 99% with an HScore of ≥ 250 in noncritically ill adults.⁵ A recently published retrospective study demonstrated the diagnostic reliability of both the HLH-2004 criteria and HScore in critically ill adult patients. This study concluded that the best prediction accuracy of HLH diagnosis for a cutoff of 4 fulfilled HLH-2004 criteria had a 95.0% sensitivity and 93.6% specificity and HScore cutoff of 168 reached a 100% sensitivity and 94.1% specificity.⁶

 

The early negative bronchoscopy lowered the possibility of an infection as the etiology of the clinical presentation and narrowed the hyperferritinemia differential diagnosis. Hyperferritinemia has a sensitivity and specificity of > 90% for diagnosis when above 10,000 ng/dL in the pediatric population.⁷ This is not the case in adults. Hyperferritinemia is a marker of different inflammatory responses, such as histoplasmosis infection, malignancy, or iron overload rather than an isolated diagnostic tool for HLH.⁸ It has been reported that CD25 levels less than the diagnostic threshold of 2400 U/mL have a 100% sensitivity for the diagnosis and therefore can rule out the diagnosis. When this is taken into consideration, it can be concluded that CD25 level is a better diagnostic tool when compared with ferritin, but its main limitation is its lack of widespread availability.⁹ Still, there is a limited number of pathologies that are associated with marked hyperferritinemia, specifically using thresholds of more than 6000 ng/dL.¹⁰ Taking into consideration the high mortality of untreated HLH, isolated hyperferritinemia still warrants HLH workup to aggressively pursue the diagnosis and improve outcomes.

The goal of therapy in HLH is prompt inactivation of the dysregulated inflammation with aggressive immunosuppression. In our deteriorating patient, the treatment was started with only 4 of the 8 HLH-2004 diagnostic criteria being met. As per the 2018 Histiocyte Society consensus statement, the decision to start the HLH-94 treatment relies on not only the HLH-2004 diagnostic criteria, but also the patient’s clinical evolution.¹¹ In 1994 the Histiocyte Society also published a treatment protocol termed HLH-94. A Korean retrospective study demonstrated that this protocol led to a 5-year survival rate of 60 to 80% depending on the HLH trigger and response to initial treatment.¹² The protocol consists of etoposide at 150 mg/m², 2 weekly doses in the first 2 weeks and then 1 dose weekly for the next 6 weeks. Dexamethasone is the steroid of choice as it readily crosses the blood-brain barrier. Its dosage consists of 10 mg/m² for the first 2 weeks and then it is halved every 2 weeks until the eighth week of treatment. A slow taper follows to avoid adrenal insufficiency. Once 8 weeks of treatment have been completed, cyclosporine is added to a goal trough of 200 mcg/dL. If there is central nervous system (CNS) involvement, early aggressive treatment with intrathecal methotrexate is indicated if no improvement is noted during initial therapy.¹¹

In 2004 the Histiocyte Society restructured the HLH-94 treatment protocol with the aim of presenting a more aggressive treatment strategy. The protocol added cyclosporine to the initial induction therapy, rather than later in the ninth week as HLH-94. Neither the use of cyclosporine nor the HLH-2004 have been demonstrated to be superior to the use of etoposide and dexamethasone alone or in the HLH-94 protocol, respectively.¹³ Cyclosporine is associated with adverse effects (AEs) and may have many contraindications in the acute phase of the disease. Therefore, the HLH-94 protocol is still the recommended regimen.¹¹

To assess adequate clinical response, several clinical and laboratory parameters are followed. Clinically, resolution of fever, improvement in hepatosplenomegaly, lymphadenopathy, and mental status can be useful. Laboratories can be used to assess improvement from organ specific damage such as hepatic involvement or cytopenia. The limitation of these diagnostic studies is that they could falsely suggest an inadequate response to treatment due to concomitant infection or medication AEs. Other markers such as ferritin levels, CD25, and NK cell activity levels are more specific to HLH. Out of them, a decreasing ferritin level has the needed specificity and widespread availability for repeated assessment. On the other hand, both CD25 and NK cell activity are readily available only in specialized centers. An initial high ferritin level is a marker for a poor prognosis, and the rate of decline correlates with mortality. Studies have demonstrated that persistently elevated ferritin levels after treatment initiation are associated with worse outcomes.^14,15

Several salvage treatments have been identified in recalcitrant or relapsing disease. In general, chemotherapy needs to be intensified, either by returning to the initial high dosage if recurrence occurs in the weaning phase of treatment or adding other agents if no response was initially achieved. Emapalumab, an interferon γ antibody, was approved by the US Food and Drug Administration for the treatment of intractable HLH after it demonstrated that when added to dexamethasone, it lead to treatment response in 17 out of 27 pediatric patients, with a relatively safe AE profile.¹⁶ The goal of intensifying chemotherapy is to have the patient tolerate allogenic stem cell transplant, which is clinically indicated in familial HLH, malignancy induced HLH, and recalcitrant cases. In patients who undergo hematopoietic cell transplantation (HCT) there is a tendency to increase survival to 66% at 5 years.¹²

Conclusions

HLH is a rare and deadly disease increasingly more present in adults. Our patient who initially presented with a sepsis diagnosis was suspected of having a hematologic etiology for his clinical findings due to markedly elevated ferritin levels. In our patient, the HLH-94 treatment protocol was used, yielding favorable results. Given the lack of specific scientific data backing updated protocols such as HLH-2004 and a comparatively favorable safety profile, current guidelines still recommend using the HLH-94 treatment protocol. Decreasing ferritin levels may be used in conjunction with clinical improvement to demonstrate therapeutic response. Persistence of disease despite standard treatment may warrant novel therapies, such as emapalumab or HCT. Physicians need to be wary of an HLH diagnosis as early identification and treatment may improve its otherwise grim prognosis.

Airway foreign-body aspiration may cause no symptoms, although it can produce acute and life-threatening central airway obstruction.¹ In the US, at least 2,700 people, including more than 300 children, die of foreign-body aspiration each year.² Most foreign-body aspirations occur in children and elderly patients.³ In adults, dementia, drug intoxication, strokes, seizures, and neurologic disorders may predispose patients to aspiration.³ Some of the consequences of an aspirated object are complete or partial airway obstruction, respiratory distress and failure, pneumothorax, and hemorrhage.² In addition, inadvertent aspiration of foreign objects in asymptomatic patients may not be evident for months, resulting in late complications as postobstructive pneumonia, bronchiectasis, or lung abscess.²

We present a case of a patient with documented schizophrenia with nonadherence to his antipsychotic medications who aspirated different objects. Flexible bronchoscopy was performed since rigid bronchoscopy is not available at our institution. Several bronchoscopy tools were required to successfully remove the objects and avoid further invasive interventions, such as cardiothoracic surgery.

Case Presentation

A 55-year-old man with schizophrenia on antipsychotics developed cough, shortness of breath, and dysphagia of 1-month of evolution. Because his symptoms worsened, his mother brought him to the emergency department. Peripheral oxygen saturation was 97% at room air. Lung auscultation was remarkable for bilateral scattered rhonchi and wheezes.

Laboratory results showed leukocytosis with neutrophilia and hypotonic hypovolemic hyponatremia. 

In view of shortness of breath, cough, wheezes, and leukocytosis, a chest radiograph was performed, showing a rounded metallic density and 2 metallic objects (appearing to be a screw and a nail) at the right main stem bronchus for which the pneumology service was consulted (Figures 1A and 1B).

The patient stated that he did not remember swallowing any objects, although his mother confirmed that he was not adherent with his antipsychotic medications, which could have predisposed him to aspiration secondary to possible psychotic episodes. 

A chest computer tomography (CT) scan without contrast confirmed the presence of the materials (Figures 2A and 2B) and a possible prevertebral abscess, which could explain the patient’s dysphagia.

Piperacillin/tazobactam 4.5 g every 8 hours was started to cover anaerobic bacterial organisms causing abscess, and IV fluids were given for hypovolemia. Flexible bronchoscopy (rigid bronchoscopy is superior although not available at our institution) was planned to be performed in the operating room (OR) because we predicted a difficult and prolonged retrieval in view of multiple and different-sized objects.

A bronchoscopy was performed, showing a disk-shaped metallic foreign body at the right main stem bronchus. After multiple attempts using the tripod retrieval tool, a coin was removed (Figures 3A and 3B). 

Using a snare retrieving tool, the surgeons removed a screw from the right main stem bronchus as well (Figures 4A and 4B). 

A third foreign object with the appearance of a nail (Figure 5) was visualized distal in the right main stem bronchus. Because of the difficult position where the object was lodged, initial attempts to retrieve the object were unsuccessful. The airway was secured with endotracheal intubation, and the patient was sedated. 

Then multiple attempts at retrieval of this foreign object were performed with the tripod and snare tools. The object was finally advanced toward the endotracheal tube (ETT), yet it was larger than the caliber of the ETT. Therefore, the cuff was deflated, and the ETT was removed at the same time the bronchoscope was retrieved while holding the last foreign body.

The patient was reintubated without any complications. A postprocedure chest radiograph showed the absence of foreign bodies and no pneumothorax. The patient completed IV antibiotic with piperacillin/tazobactam and supportive therapy with clinical improvement and successful extubation within 2 days. Cardiothoracic surgery was not required. Psychiatry service recommended to continue the same antipsychotic medications, administered only by his mother to assure adherence and to avoid similar future events. The patient was discharged home without any immediate complications despite having had a coin, nail, and screw aspiration (Figure 6).

 

Discussion

More than 50% of foreign bodies lodge at the right main stem bronchus due to the trachea’s anatomical position.^2,4 In adults, foreign-body aspiration may present with nonspecific symptoms, such as cough and dyspnea.⁴ Other symptoms might include wheezes, chest discomfort, and sputum production. A chest radiograph is helpful as part of the initial diagnostic workup. A chest CT scan without contrast should be performed to confirm the diagnosis and to plan possible foreign-body retrieval.

Bronchoscopy is the gold standard for diagnosis and management of foreign-body aspiration.¹ Rigid bronchoscopy is superior to flexible bronchoscopy in removal of large airway foreign bodies.¹ The rigid bronchoscopy provides the ability to function as an endotracheal tube, thus allowing control of the airway and a conduit through which foreign bodies can be removed.¹ Nonetheless, sometimes retrieval of foreign bodies deeper into the subsegmental bronchi cannot be achieved.¹ Moreover, the required equipment or knowledgeable staff is not always available.¹ Therefore, flexible bronchoscopy is an option to retrieve airway foreign bodies especially those located distal in the airway and for those medical centers without rigid bronchoscopy as is the case in our institution.

In our case, flexible bronchoscopy was performed in the OR because we predicted a difficult and prolonged retrieval in view of multiple and different-sized objects. Anesthesia Service assistance was requested anticipating need for patient sedation and intubation. We used the tripod and snare retrieval tools to remove 3 foreign objects located at the right main stem bronchus. Even though multiple attempts were made and endotracheal intubation was required, a successful retrieval with flexible bronchoscopy was performed. Moreover, cardiothoracic surgery was not required avoiding more invasive interventions with subsequent morbidity and mortality.

Conclusion

Flexible bronchoscopy is an important tool within the arsenal of the Pulmonology Service. The management of the underlying etiology also should be performed. In our case, the Psychiatry Service recommended that the patient’s medications should be administered by his mother to avoid similar events in the future. Flexible bronchoscopy can be a valuable option for foreign objects removal, especially those distally located in the lung segments as well as in those medical centers where rigid bronchoscopy is not available.

Airway foreign-body aspiration may cause no symptoms, although it can produce acute and life-threatening central airway obstruction.¹ In the US, at least 2,700 people, including more than 300 children, die of foreign-body aspiration each year.² Most foreign-body aspirations occur in children and elderly patients.³ In adults, dementia, drug intoxication, strokes, seizures, and neurologic disorders may predispose patients to aspiration.³ Some of the consequences of an aspirated object are complete or partial airway obstruction, respiratory distress and failure, pneumothorax, and hemorrhage.² In addition, inadvertent aspiration of foreign objects in asymptomatic patients may not be evident for months, resulting in late complications as postobstructive pneumonia, bronchiectasis, or lung abscess.²

We present a case of a patient with documented schizophrenia with nonadherence to his antipsychotic medications who aspirated different objects. Flexible bronchoscopy was performed since rigid bronchoscopy is not available at our institution. Several bronchoscopy tools were required to successfully remove the objects and avoid further invasive interventions, such as cardiothoracic surgery.

Case Presentation

A 55-year-old man with schizophrenia on antipsychotics developed cough, shortness of breath, and dysphagia of 1-month of evolution. Because his symptoms worsened, his mother brought him to the emergency department. Peripheral oxygen saturation was 97% at room air. Lung auscultation was remarkable for bilateral scattered rhonchi and wheezes.

Laboratory results showed leukocytosis with neutrophilia and hypotonic hypovolemic hyponatremia. 

In view of shortness of breath, cough, wheezes, and leukocytosis, a chest radiograph was performed, showing a rounded metallic density and 2 metallic objects (appearing to be a screw and a nail) at the right main stem bronchus for which the pneumology service was consulted (Figures 1A and 1B).

The patient stated that he did not remember swallowing any objects, although his mother confirmed that he was not adherent with his antipsychotic medications, which could have predisposed him to aspiration secondary to possible psychotic episodes. 

A chest computer tomography (CT) scan without contrast confirmed the presence of the materials (Figures 2A and 2B) and a possible prevertebral abscess, which could explain the patient’s dysphagia.

Piperacillin/tazobactam 4.5 g every 8 hours was started to cover anaerobic bacterial organisms causing abscess, and IV fluids were given for hypovolemia. Flexible bronchoscopy (rigid bronchoscopy is superior although not available at our institution) was planned to be performed in the operating room (OR) because we predicted a difficult and prolonged retrieval in view of multiple and different-sized objects.

A bronchoscopy was performed, showing a disk-shaped metallic foreign body at the right main stem bronchus. After multiple attempts using the tripod retrieval tool, a coin was removed (Figures 3A and 3B). 

Using a snare retrieving tool, the surgeons removed a screw from the right main stem bronchus as well (Figures 4A and 4B). 

A third foreign object with the appearance of a nail (Figure 5) was visualized distal in the right main stem bronchus. Because of the difficult position where the object was lodged, initial attempts to retrieve the object were unsuccessful. The airway was secured with endotracheal intubation, and the patient was sedated. 

Then multiple attempts at retrieval of this foreign object were performed with the tripod and snare tools. The object was finally advanced toward the endotracheal tube (ETT), yet it was larger than the caliber of the ETT. Therefore, the cuff was deflated, and the ETT was removed at the same time the bronchoscope was retrieved while holding the last foreign body.

The patient was reintubated without any complications. A postprocedure chest radiograph showed the absence of foreign bodies and no pneumothorax. The patient completed IV antibiotic with piperacillin/tazobactam and supportive therapy with clinical improvement and successful extubation within 2 days. Cardiothoracic surgery was not required. Psychiatry service recommended to continue the same antipsychotic medications, administered only by his mother to assure adherence and to avoid similar future events. The patient was discharged home without any immediate complications despite having had a coin, nail, and screw aspiration (Figure 6).

 

Discussion

More than 50% of foreign bodies lodge at the right main stem bronchus due to the trachea’s anatomical position.^2,4 In adults, foreign-body aspiration may present with nonspecific symptoms, such as cough and dyspnea.⁴ Other symptoms might include wheezes, chest discomfort, and sputum production. A chest radiograph is helpful as part of the initial diagnostic workup. A chest CT scan without contrast should be performed to confirm the diagnosis and to plan possible foreign-body retrieval.

Bronchoscopy is the gold standard for diagnosis and management of foreign-body aspiration.¹ Rigid bronchoscopy is superior to flexible bronchoscopy in removal of large airway foreign bodies.¹ The rigid bronchoscopy provides the ability to function as an endotracheal tube, thus allowing control of the airway and a conduit through which foreign bodies can be removed.¹ Nonetheless, sometimes retrieval of foreign bodies deeper into the subsegmental bronchi cannot be achieved.¹ Moreover, the required equipment or knowledgeable staff is not always available.¹ Therefore, flexible bronchoscopy is an option to retrieve airway foreign bodies especially those located distal in the airway and for those medical centers without rigid bronchoscopy as is the case in our institution.

In our case, flexible bronchoscopy was performed in the OR because we predicted a difficult and prolonged retrieval in view of multiple and different-sized objects. Anesthesia Service assistance was requested anticipating need for patient sedation and intubation. We used the tripod and snare retrieval tools to remove 3 foreign objects located at the right main stem bronchus. Even though multiple attempts were made and endotracheal intubation was required, a successful retrieval with flexible bronchoscopy was performed. Moreover, cardiothoracic surgery was not required avoiding more invasive interventions with subsequent morbidity and mortality.

Conclusion

Flexible bronchoscopy is an important tool within the arsenal of the Pulmonology Service. The management of the underlying etiology also should be performed. In our case, the Psychiatry Service recommended that the patient’s medications should be administered by his mother to avoid similar events in the future. Flexible bronchoscopy can be a valuable option for foreign objects removal, especially those distally located in the lung segments as well as in those medical centers where rigid bronchoscopy is not available.

Airway foreign-body aspiration may cause no symptoms, although it can produce acute and life-threatening central airway obstruction.¹ In the US, at least 2,700 people, including more than 300 children, die of foreign-body aspiration each year.² Most foreign-body aspirations occur in children and elderly patients.³ In adults, dementia, drug intoxication, strokes, seizures, and neurologic disorders may predispose patients to aspiration.³ Some of the consequences of an aspirated object are complete or partial airway obstruction, respiratory distress and failure, pneumothorax, and hemorrhage.² In addition, inadvertent aspiration of foreign objects in asymptomatic patients may not be evident for months, resulting in late complications as postobstructive pneumonia, bronchiectasis, or lung abscess.²

We present a case of a patient with documented schizophrenia with nonadherence to his antipsychotic medications who aspirated different objects. Flexible bronchoscopy was performed since rigid bronchoscopy is not available at our institution. Several bronchoscopy tools were required to successfully remove the objects and avoid further invasive interventions, such as cardiothoracic surgery.

Case Presentation

A 55-year-old man with schizophrenia on antipsychotics developed cough, shortness of breath, and dysphagia of 1-month of evolution. Because his symptoms worsened, his mother brought him to the emergency department. Peripheral oxygen saturation was 97% at room air. Lung auscultation was remarkable for bilateral scattered rhonchi and wheezes.

Laboratory results showed leukocytosis with neutrophilia and hypotonic hypovolemic hyponatremia. 

In view of shortness of breath, cough, wheezes, and leukocytosis, a chest radiograph was performed, showing a rounded metallic density and 2 metallic objects (appearing to be a screw and a nail) at the right main stem bronchus for which the pneumology service was consulted (Figures 1A and 1B).

The patient stated that he did not remember swallowing any objects, although his mother confirmed that he was not adherent with his antipsychotic medications, which could have predisposed him to aspiration secondary to possible psychotic episodes. 

A chest computer tomography (CT) scan without contrast confirmed the presence of the materials (Figures 2A and 2B) and a possible prevertebral abscess, which could explain the patient’s dysphagia.

Piperacillin/tazobactam 4.5 g every 8 hours was started to cover anaerobic bacterial organisms causing abscess, and IV fluids were given for hypovolemia. Flexible bronchoscopy (rigid bronchoscopy is superior although not available at our institution) was planned to be performed in the operating room (OR) because we predicted a difficult and prolonged retrieval in view of multiple and different-sized objects.

A bronchoscopy was performed, showing a disk-shaped metallic foreign body at the right main stem bronchus. After multiple attempts using the tripod retrieval tool, a coin was removed (Figures 3A and 3B). 

Using a snare retrieving tool, the surgeons removed a screw from the right main stem bronchus as well (Figures 4A and 4B). 

A third foreign object with the appearance of a nail (Figure 5) was visualized distal in the right main stem bronchus. Because of the difficult position where the object was lodged, initial attempts to retrieve the object were unsuccessful. The airway was secured with endotracheal intubation, and the patient was sedated. 

Then multiple attempts at retrieval of this foreign object were performed with the tripod and snare tools. The object was finally advanced toward the endotracheal tube (ETT), yet it was larger than the caliber of the ETT. Therefore, the cuff was deflated, and the ETT was removed at the same time the bronchoscope was retrieved while holding the last foreign body.

The patient was reintubated without any complications. A postprocedure chest radiograph showed the absence of foreign bodies and no pneumothorax. The patient completed IV antibiotic with piperacillin/tazobactam and supportive therapy with clinical improvement and successful extubation within 2 days. Cardiothoracic surgery was not required. Psychiatry service recommended to continue the same antipsychotic medications, administered only by his mother to assure adherence and to avoid similar future events. The patient was discharged home without any immediate complications despite having had a coin, nail, and screw aspiration (Figure 6).

 

Discussion

More than 50% of foreign bodies lodge at the right main stem bronchus due to the trachea’s anatomical position.^2,4 In adults, foreign-body aspiration may present with nonspecific symptoms, such as cough and dyspnea.⁴ Other symptoms might include wheezes, chest discomfort, and sputum production. A chest radiograph is helpful as part of the initial diagnostic workup. A chest CT scan without contrast should be performed to confirm the diagnosis and to plan possible foreign-body retrieval.

Bronchoscopy is the gold standard for diagnosis and management of foreign-body aspiration.¹ Rigid bronchoscopy is superior to flexible bronchoscopy in removal of large airway foreign bodies.¹ The rigid bronchoscopy provides the ability to function as an endotracheal tube, thus allowing control of the airway and a conduit through which foreign bodies can be removed.¹ Nonetheless, sometimes retrieval of foreign bodies deeper into the subsegmental bronchi cannot be achieved.¹ Moreover, the required equipment or knowledgeable staff is not always available.¹ Therefore, flexible bronchoscopy is an option to retrieve airway foreign bodies especially those located distal in the airway and for those medical centers without rigid bronchoscopy as is the case in our institution.

In our case, flexible bronchoscopy was performed in the OR because we predicted a difficult and prolonged retrieval in view of multiple and different-sized objects. Anesthesia Service assistance was requested anticipating need for patient sedation and intubation. We used the tripod and snare retrieval tools to remove 3 foreign objects located at the right main stem bronchus. Even though multiple attempts were made and endotracheal intubation was required, a successful retrieval with flexible bronchoscopy was performed. Moreover, cardiothoracic surgery was not required avoiding more invasive interventions with subsequent morbidity and mortality.

Conclusion

Flexible bronchoscopy is an important tool within the arsenal of the Pulmonology Service. The management of the underlying etiology also should be performed. In our case, the Psychiatry Service recommended that the patient’s medications should be administered by his mother to avoid similar events in the future. Flexible bronchoscopy can be a valuable option for foreign objects removal, especially those distally located in the lung segments as well as in those medical centers where rigid bronchoscopy is not available.

Purulent pericarditis is an infection within the pericardial space rarely seen in the modern antibiotic era. Most cases are secondary to another infectious process of bacterial, viral, fungal, or parasitic origin.^1,2 Predisposing factors include malignancy, chronic kidney disease, immunosuppression, diabetes mellitus, and alcohol misuse disorder.¹ Although purulent pericarditis has been described extensively in the literature, it is a challenging diagnosis if it is not initially considered within the differential diagnosis repertoire.^1-4 Most authors agree that this may be because it has become an infrequent diagnosis.^1,2 In addition, purulent pericarditis may have an atypical presentation when compared with a classic case of pericarditis.^2,3 The authors believe that this forgotten entity will be revisited through this case.

Case Presentation

A 66-year-old-man was transferred to Veterans Affairs Caribbean Healthcare System (VACHS) from a community hospital with a diagnosis of community-acquired pneumonia (CAP) and bilateral pleural effusions. Four days prior to arrival at the community hospital, the patient had developed diffuse, watery diarrhea, which resolved in 3 days. After resolution of diarrhea, he began experiencing shortness of breath on exertion that progressed to onset at rest. The patient reported no fever, chills, nausea, vomiting, cough, or contact with others who were not healthy. He had a history of alcohol misuse without liver cirrhosis and reported no chronic diseases or use of medications. The patient had no history of tuberculosis exposure or pneumococcal vaccination, and had a negative interferon gamma release assay.

On admission to the community hospital, the patient was treated for CAP with ceftriaxone and azithromycin. On hospital day 3, the patient developed hypoxemia and an altered mental status. He was started on supplemental oxygen and transferred to the intensive care unit (ICU). Antibiotic therapy consequently was changed to levofloxacin and meropenem. However, no clinical improvement was noted on the following days.

On hospital day 7, the patient developed acute respiratory failure that required mechanical ventilation while being transferred to VACHS via air ambulance. His vital signs on arrival were the following: temperature, 97° F; heart rate, 86 beats/min; blood pressure, 103/61 mm Hg; respiratory rate, 14 breaths/min and SaO₂ of 97%, measured while he breathed supplemental oxygen at an FiO₂ of 0.4. 

Laboratory results revealed a white blood cell count (WBC) of 11.2 × 103/µL, with 92% neutrophils, 4% bands, 1% lymphocytes; lactic acid, 1.3 mmol/L; and high sensitivity C-reactive protein, 43.1 mg/L. A chest radiograph demonstrated bibasilar pulmonary opacities, bilateral pleural effusions, and cardiomegaly (Figure 1).

Hours after arrival, the patient developed sinus tachycardia and hypotension. A bedside 2D echocardiogram demonstrated a large pericardial effusion with diastolic collapse of the right atrium (Figure 2). 

Aggressive fluid resuscitation with normal saline and inotropic support with dopamine were started as an immediate percutaneous pericardiocentesis was performed with drainage of 400 mL of frank purulent fluid (Figure 3).

After percutaneous pericardiocentesis was completed, a temporary catheter was placed into the pericardial space using the Seldinger technique in order to aspirate fluid as needed.

The patient’s clinical condition improved following drainage of pericardial fluid, with no further need for inotropic support. Antibiotic therapy was changed to vancomycin and meropenem. Initial microbiologic samples from pericardial fluid demonstrated Gram-positive diplococci, suggestive of Streptococcus pneumoniae (S pneumoniae) (Figure 4). Other diagnostic pericardial fluid test results included: WBC count 25,330 cmm, with 99% neutrophils and 1% lymphocytes; total protein, 3.8 mg/dL; glucose, < 2.0 mg/dL,LDH, > 2,500 U/L, potassium hydroxide preparation. The tests found no fungus, and the acid fast bacilli smear revealed no Bacillus. However, the pericardial fluid culture failed to demonstrate growth of any organism. Blood cultures also were negative.

The patient underwent anterior thoracotomy with partial pericardiectomy, and a pericardial tube was left in place connected to drainage. During the procedure, an abundant amount of fibrinous tissue was evacuated from the pericardial space (Figure 5). 

The patient’s status improved the following day, and inotropic support once again was stopped. Bilateral pleural tubes were placed for evacuation of loculated effusions. Laboratory results from left-sided fluid were suggestive of complicated parapneumonic effusion with a WBC count of 6,683 cmm and glucose, 12 mg/dL. Right-sided pleural fluid was consistent with exudate with a WBC count of 2,006 cmm; pH 7.49; LDH, 1450 U/L; and glucose, 66 mg/dL. Gram stain and cultures of pleural fluid were negative.

The patient was extubated, pericardial and pleural tubes were removed, and he was transferred to the internal medicine ward 24 days after admission to the ICU. He received in-patient physical rehabilitation while completing a 6-week course of IV antibiotics (vancomycin and meropenem). After completion of therapy, the patient received the pneumococcal polysaccharide vaccination, and an echocardiography was repeated. No significant re-accumulation of pericardial effusion or constrictive pattern was evidenced. The patient was discharged to his out-of-state home, and follow-up was consequently lost.

 

Discussion

Purulent pericarditis is an infection localized within the pericardial space. Most cases are secondary to an infectious process elsewhere, which could be of bacterial, viral, fungal, or parasitic etiology.¹ Five mechanisms could lead the infecting organism to infect the pericardial space; contiguous spread from intrathoracic site, hematogenous spread, extension from myocardial site, perforating injury or surgery, and extension from a subdiaphragmatic site.¹ Predisposing factors for the development of this condition include malignancy, chronic kidney disease, immunosuppression, diabetes mellitus, and alcohol misuse. Pericarditis is an infection localized within the pericardial space.

Purulent pericarditis has become a rare entity in the antibiotic era.² Prior to the development of antibiotics, most cases were secondary to S pneumoniae.^1,2,5,6 As per Cilloniz and colleagues, about 40% to 50% of all cases of purulent pericarditis are caused by Gram-positive bacteria, mostly S pneumoniae.⁵ In this case study, bacterial culture did not reveal growth of an organism—most likely because the patient had received antibiotics elsewhere. However, Gram-positive cocci were seen within the initial pericardial aspirate. This organism was suspected to have spread contiguously from a pulmonary focus, which also led to pleural effusions.

Since the patient in this case study had no history of thoracic surgery, malignancy, or other immunosuppression, the patient’s history of alcohol misuse was the only predisposing factor for development of purulent pericarditis. Contrary to the common presentation of pericarditis, purulent pericarditis may not have the common clinical findings, such as chest pain, pericardial friction rub, and distended neck veins.^2,3 Furthermore, according to Parikh and colleagues, about 35% of affected patients may have a normal electrocardiogram.² Hence, the diagnosis of purulent pericarditis often is missed because the classic signs of pericarditis are often absent, and other nonspecific symptoms are attributed to initial underlying infection.⁷

A high index of suspicion is needed to diagnose purulent pericarditis. Once a diagnosis is made, initial treatment should consist of prompt drainage of pericardial fluid combined with systemic antibiotic therapy. Vancomycin and a third-generation cephalosporin may be started empirically until results of pericardial fluid cultures become available.³ Drainage can be achieved by pericardiocentesis, pericardiotomy, or pericardiectomy (partial or total).¹ In cases of hemodynamic instability due to cardiac tamponade, sonographically guided pericardiocentesis should be undertaken and an indwelling pericardial catheter left in place.¹ Although this is the simplest and fastest method of evacuation, it may not be effective when dealing with thick, fibrinous fluid. In such cases, intrapericardial fibrinolysis may be considered. This approach may be undertaken early in the process, after drainage insertion, or as salvage therapy, when there has been incomplete evacuation of purulent material or open surgical drainage is not available.

Streptokinase, urokinase, and tissue plasminogen activator have been used for intrapericadial fibrinolysis.¹ However, there is no definite data on dosage or frequency at which these medications should be administered. No matter the therapeutic approach, effective drainage of the pericardial fluid is crucial to avoid the development of pericardial constriction. Constrictive pericarditis occurs when fibrosis and adhesions create a dense pericardium that encases the heart. This causes impaired ventricular filling that can lead eventually to heart failure.⁴ Pericardiectomy is the definitive treatment for constrictive pericarditis.

Conclusion

Although purulent pericarditis has become a rare diagnosis since the development of antibiotics, knowledge of how to identify it is essential since mortality reaches 100% if the diagnosis is missed.⁴ Even when the condition is promptly diagnosed and treated, mortality is 40%, mainly due to cardiac tamponade, septic shock, or constriction.¹ The case presented here illustrates the clinical features associated with this condition. Knowing these features can translate in a successful patient outcome.

Purulent pericarditis is an infection within the pericardial space rarely seen in the modern antibiotic era. Most cases are secondary to another infectious process of bacterial, viral, fungal, or parasitic origin.^1,2 Predisposing factors include malignancy, chronic kidney disease, immunosuppression, diabetes mellitus, and alcohol misuse disorder.¹ Although purulent pericarditis has been described extensively in the literature, it is a challenging diagnosis if it is not initially considered within the differential diagnosis repertoire.^1-4 Most authors agree that this may be because it has become an infrequent diagnosis.^1,2 In addition, purulent pericarditis may have an atypical presentation when compared with a classic case of pericarditis.^2,3 The authors believe that this forgotten entity will be revisited through this case.

Case Presentation

A 66-year-old-man was transferred to Veterans Affairs Caribbean Healthcare System (VACHS) from a community hospital with a diagnosis of community-acquired pneumonia (CAP) and bilateral pleural effusions. Four days prior to arrival at the community hospital, the patient had developed diffuse, watery diarrhea, which resolved in 3 days. After resolution of diarrhea, he began experiencing shortness of breath on exertion that progressed to onset at rest. The patient reported no fever, chills, nausea, vomiting, cough, or contact with others who were not healthy. He had a history of alcohol misuse without liver cirrhosis and reported no chronic diseases or use of medications. The patient had no history of tuberculosis exposure or pneumococcal vaccination, and had a negative interferon gamma release assay.

On admission to the community hospital, the patient was treated for CAP with ceftriaxone and azithromycin. On hospital day 3, the patient developed hypoxemia and an altered mental status. He was started on supplemental oxygen and transferred to the intensive care unit (ICU). Antibiotic therapy consequently was changed to levofloxacin and meropenem. However, no clinical improvement was noted on the following days.

On hospital day 7, the patient developed acute respiratory failure that required mechanical ventilation while being transferred to VACHS via air ambulance. His vital signs on arrival were the following: temperature, 97° F; heart rate, 86 beats/min; blood pressure, 103/61 mm Hg; respiratory rate, 14 breaths/min and SaO₂ of 97%, measured while he breathed supplemental oxygen at an FiO₂ of 0.4. 

Laboratory results revealed a white blood cell count (WBC) of 11.2 × 103/µL, with 92% neutrophils, 4% bands, 1% lymphocytes; lactic acid, 1.3 mmol/L; and high sensitivity C-reactive protein, 43.1 mg/L. A chest radiograph demonstrated bibasilar pulmonary opacities, bilateral pleural effusions, and cardiomegaly (Figure 1).

Hours after arrival, the patient developed sinus tachycardia and hypotension. A bedside 2D echocardiogram demonstrated a large pericardial effusion with diastolic collapse of the right atrium (Figure 2). 

Aggressive fluid resuscitation with normal saline and inotropic support with dopamine were started as an immediate percutaneous pericardiocentesis was performed with drainage of 400 mL of frank purulent fluid (Figure 3).

After percutaneous pericardiocentesis was completed, a temporary catheter was placed into the pericardial space using the Seldinger technique in order to aspirate fluid as needed.

The patient’s clinical condition improved following drainage of pericardial fluid, with no further need for inotropic support. Antibiotic therapy was changed to vancomycin and meropenem. Initial microbiologic samples from pericardial fluid demonstrated Gram-positive diplococci, suggestive of Streptococcus pneumoniae (S pneumoniae) (Figure 4). Other diagnostic pericardial fluid test results included: WBC count 25,330 cmm, with 99% neutrophils and 1% lymphocytes; total protein, 3.8 mg/dL; glucose, < 2.0 mg/dL,LDH, > 2,500 U/L, potassium hydroxide preparation. The tests found no fungus, and the acid fast bacilli smear revealed no Bacillus. However, the pericardial fluid culture failed to demonstrate growth of any organism. Blood cultures also were negative.

The patient underwent anterior thoracotomy with partial pericardiectomy, and a pericardial tube was left in place connected to drainage. During the procedure, an abundant amount of fibrinous tissue was evacuated from the pericardial space (Figure 5). 

The patient’s status improved the following day, and inotropic support once again was stopped. Bilateral pleural tubes were placed for evacuation of loculated effusions. Laboratory results from left-sided fluid were suggestive of complicated parapneumonic effusion with a WBC count of 6,683 cmm and glucose, 12 mg/dL. Right-sided pleural fluid was consistent with exudate with a WBC count of 2,006 cmm; pH 7.49; LDH, 1450 U/L; and glucose, 66 mg/dL. Gram stain and cultures of pleural fluid were negative.

The patient was extubated, pericardial and pleural tubes were removed, and he was transferred to the internal medicine ward 24 days after admission to the ICU. He received in-patient physical rehabilitation while completing a 6-week course of IV antibiotics (vancomycin and meropenem). After completion of therapy, the patient received the pneumococcal polysaccharide vaccination, and an echocardiography was repeated. No significant re-accumulation of pericardial effusion or constrictive pattern was evidenced. The patient was discharged to his out-of-state home, and follow-up was consequently lost.

 

Discussion

Purulent pericarditis is an infection localized within the pericardial space. Most cases are secondary to an infectious process elsewhere, which could be of bacterial, viral, fungal, or parasitic etiology.¹ Five mechanisms could lead the infecting organism to infect the pericardial space; contiguous spread from intrathoracic site, hematogenous spread, extension from myocardial site, perforating injury or surgery, and extension from a subdiaphragmatic site.¹ Predisposing factors for the development of this condition include malignancy, chronic kidney disease, immunosuppression, diabetes mellitus, and alcohol misuse. Pericarditis is an infection localized within the pericardial space.

Purulent pericarditis has become a rare entity in the antibiotic era.² Prior to the development of antibiotics, most cases were secondary to S pneumoniae.^1,2,5,6 As per Cilloniz and colleagues, about 40% to 50% of all cases of purulent pericarditis are caused by Gram-positive bacteria, mostly S pneumoniae.⁵ In this case study, bacterial culture did not reveal growth of an organism—most likely because the patient had received antibiotics elsewhere. However, Gram-positive cocci were seen within the initial pericardial aspirate. This organism was suspected to have spread contiguously from a pulmonary focus, which also led to pleural effusions.

Since the patient in this case study had no history of thoracic surgery, malignancy, or other immunosuppression, the patient’s history of alcohol misuse was the only predisposing factor for development of purulent pericarditis. Contrary to the common presentation of pericarditis, purulent pericarditis may not have the common clinical findings, such as chest pain, pericardial friction rub, and distended neck veins.^2,3 Furthermore, according to Parikh and colleagues, about 35% of affected patients may have a normal electrocardiogram.² Hence, the diagnosis of purulent pericarditis often is missed because the classic signs of pericarditis are often absent, and other nonspecific symptoms are attributed to initial underlying infection.⁷

A high index of suspicion is needed to diagnose purulent pericarditis. Once a diagnosis is made, initial treatment should consist of prompt drainage of pericardial fluid combined with systemic antibiotic therapy. Vancomycin and a third-generation cephalosporin may be started empirically until results of pericardial fluid cultures become available.³ Drainage can be achieved by pericardiocentesis, pericardiotomy, or pericardiectomy (partial or total).¹ In cases of hemodynamic instability due to cardiac tamponade, sonographically guided pericardiocentesis should be undertaken and an indwelling pericardial catheter left in place.¹ Although this is the simplest and fastest method of evacuation, it may not be effective when dealing with thick, fibrinous fluid. In such cases, intrapericardial fibrinolysis may be considered. This approach may be undertaken early in the process, after drainage insertion, or as salvage therapy, when there has been incomplete evacuation of purulent material or open surgical drainage is not available.

Streptokinase, urokinase, and tissue plasminogen activator have been used for intrapericadial fibrinolysis.¹ However, there is no definite data on dosage or frequency at which these medications should be administered. No matter the therapeutic approach, effective drainage of the pericardial fluid is crucial to avoid the development of pericardial constriction. Constrictive pericarditis occurs when fibrosis and adhesions create a dense pericardium that encases the heart. This causes impaired ventricular filling that can lead eventually to heart failure.⁴ Pericardiectomy is the definitive treatment for constrictive pericarditis.

Conclusion

Although purulent pericarditis has become a rare diagnosis since the development of antibiotics, knowledge of how to identify it is essential since mortality reaches 100% if the diagnosis is missed.⁴ Even when the condition is promptly diagnosed and treated, mortality is 40%, mainly due to cardiac tamponade, septic shock, or constriction.¹ The case presented here illustrates the clinical features associated with this condition. Knowing these features can translate in a successful patient outcome.

Purulent pericarditis is an infection within the pericardial space rarely seen in the modern antibiotic era. Most cases are secondary to another infectious process of bacterial, viral, fungal, or parasitic origin.^1,2 Predisposing factors include malignancy, chronic kidney disease, immunosuppression, diabetes mellitus, and alcohol misuse disorder.¹ Although purulent pericarditis has been described extensively in the literature, it is a challenging diagnosis if it is not initially considered within the differential diagnosis repertoire.^1-4 Most authors agree that this may be because it has become an infrequent diagnosis.^1,2 In addition, purulent pericarditis may have an atypical presentation when compared with a classic case of pericarditis.^2,3 The authors believe that this forgotten entity will be revisited through this case.

Case Presentation

A 66-year-old-man was transferred to Veterans Affairs Caribbean Healthcare System (VACHS) from a community hospital with a diagnosis of community-acquired pneumonia (CAP) and bilateral pleural effusions. Four days prior to arrival at the community hospital, the patient had developed diffuse, watery diarrhea, which resolved in 3 days. After resolution of diarrhea, he began experiencing shortness of breath on exertion that progressed to onset at rest. The patient reported no fever, chills, nausea, vomiting, cough, or contact with others who were not healthy. He had a history of alcohol misuse without liver cirrhosis and reported no chronic diseases or use of medications. The patient had no history of tuberculosis exposure or pneumococcal vaccination, and had a negative interferon gamma release assay.

On admission to the community hospital, the patient was treated for CAP with ceftriaxone and azithromycin. On hospital day 3, the patient developed hypoxemia and an altered mental status. He was started on supplemental oxygen and transferred to the intensive care unit (ICU). Antibiotic therapy consequently was changed to levofloxacin and meropenem. However, no clinical improvement was noted on the following days.

On hospital day 7, the patient developed acute respiratory failure that required mechanical ventilation while being transferred to VACHS via air ambulance. His vital signs on arrival were the following: temperature, 97° F; heart rate, 86 beats/min; blood pressure, 103/61 mm Hg; respiratory rate, 14 breaths/min and SaO₂ of 97%, measured while he breathed supplemental oxygen at an FiO₂ of 0.4. 

Laboratory results revealed a white blood cell count (WBC) of 11.2 × 103/µL, with 92% neutrophils, 4% bands, 1% lymphocytes; lactic acid, 1.3 mmol/L; and high sensitivity C-reactive protein, 43.1 mg/L. A chest radiograph demonstrated bibasilar pulmonary opacities, bilateral pleural effusions, and cardiomegaly (Figure 1).

Hours after arrival, the patient developed sinus tachycardia and hypotension. A bedside 2D echocardiogram demonstrated a large pericardial effusion with diastolic collapse of the right atrium (Figure 2). 

Aggressive fluid resuscitation with normal saline and inotropic support with dopamine were started as an immediate percutaneous pericardiocentesis was performed with drainage of 400 mL of frank purulent fluid (Figure 3).

After percutaneous pericardiocentesis was completed, a temporary catheter was placed into the pericardial space using the Seldinger technique in order to aspirate fluid as needed.

The patient’s clinical condition improved following drainage of pericardial fluid, with no further need for inotropic support. Antibiotic therapy was changed to vancomycin and meropenem. Initial microbiologic samples from pericardial fluid demonstrated Gram-positive diplococci, suggestive of Streptococcus pneumoniae (S pneumoniae) (Figure 4). Other diagnostic pericardial fluid test results included: WBC count 25,330 cmm, with 99% neutrophils and 1% lymphocytes; total protein, 3.8 mg/dL; glucose, < 2.0 mg/dL,LDH, > 2,500 U/L, potassium hydroxide preparation. The tests found no fungus, and the acid fast bacilli smear revealed no Bacillus. However, the pericardial fluid culture failed to demonstrate growth of any organism. Blood cultures also were negative.

The patient underwent anterior thoracotomy with partial pericardiectomy, and a pericardial tube was left in place connected to drainage. During the procedure, an abundant amount of fibrinous tissue was evacuated from the pericardial space (Figure 5). 

The patient’s status improved the following day, and inotropic support once again was stopped. Bilateral pleural tubes were placed for evacuation of loculated effusions. Laboratory results from left-sided fluid were suggestive of complicated parapneumonic effusion with a WBC count of 6,683 cmm and glucose, 12 mg/dL. Right-sided pleural fluid was consistent with exudate with a WBC count of 2,006 cmm; pH 7.49; LDH, 1450 U/L; and glucose, 66 mg/dL. Gram stain and cultures of pleural fluid were negative.

The patient was extubated, pericardial and pleural tubes were removed, and he was transferred to the internal medicine ward 24 days after admission to the ICU. He received in-patient physical rehabilitation while completing a 6-week course of IV antibiotics (vancomycin and meropenem). After completion of therapy, the patient received the pneumococcal polysaccharide vaccination, and an echocardiography was repeated. No significant re-accumulation of pericardial effusion or constrictive pattern was evidenced. The patient was discharged to his out-of-state home, and follow-up was consequently lost.

 

Discussion

Purulent pericarditis is an infection localized within the pericardial space. Most cases are secondary to an infectious process elsewhere, which could be of bacterial, viral, fungal, or parasitic etiology.¹ Five mechanisms could lead the infecting organism to infect the pericardial space; contiguous spread from intrathoracic site, hematogenous spread, extension from myocardial site, perforating injury or surgery, and extension from a subdiaphragmatic site.¹ Predisposing factors for the development of this condition include malignancy, chronic kidney disease, immunosuppression, diabetes mellitus, and alcohol misuse. Pericarditis is an infection localized within the pericardial space.

Purulent pericarditis has become a rare entity in the antibiotic era.² Prior to the development of antibiotics, most cases were secondary to S pneumoniae.^1,2,5,6 As per Cilloniz and colleagues, about 40% to 50% of all cases of purulent pericarditis are caused by Gram-positive bacteria, mostly S pneumoniae.⁵ In this case study, bacterial culture did not reveal growth of an organism—most likely because the patient had received antibiotics elsewhere. However, Gram-positive cocci were seen within the initial pericardial aspirate. This organism was suspected to have spread contiguously from a pulmonary focus, which also led to pleural effusions.

Since the patient in this case study had no history of thoracic surgery, malignancy, or other immunosuppression, the patient’s history of alcohol misuse was the only predisposing factor for development of purulent pericarditis. Contrary to the common presentation of pericarditis, purulent pericarditis may not have the common clinical findings, such as chest pain, pericardial friction rub, and distended neck veins.^2,3 Furthermore, according to Parikh and colleagues, about 35% of affected patients may have a normal electrocardiogram.² Hence, the diagnosis of purulent pericarditis often is missed because the classic signs of pericarditis are often absent, and other nonspecific symptoms are attributed to initial underlying infection.⁷

A high index of suspicion is needed to diagnose purulent pericarditis. Once a diagnosis is made, initial treatment should consist of prompt drainage of pericardial fluid combined with systemic antibiotic therapy. Vancomycin and a third-generation cephalosporin may be started empirically until results of pericardial fluid cultures become available.³ Drainage can be achieved by pericardiocentesis, pericardiotomy, or pericardiectomy (partial or total).¹ In cases of hemodynamic instability due to cardiac tamponade, sonographically guided pericardiocentesis should be undertaken and an indwelling pericardial catheter left in place.¹ Although this is the simplest and fastest method of evacuation, it may not be effective when dealing with thick, fibrinous fluid. In such cases, intrapericardial fibrinolysis may be considered. This approach may be undertaken early in the process, after drainage insertion, or as salvage therapy, when there has been incomplete evacuation of purulent material or open surgical drainage is not available.

Streptokinase, urokinase, and tissue plasminogen activator have been used for intrapericadial fibrinolysis.¹ However, there is no definite data on dosage or frequency at which these medications should be administered. No matter the therapeutic approach, effective drainage of the pericardial fluid is crucial to avoid the development of pericardial constriction. Constrictive pericarditis occurs when fibrosis and adhesions create a dense pericardium that encases the heart. This causes impaired ventricular filling that can lead eventually to heart failure.⁴ Pericardiectomy is the definitive treatment for constrictive pericarditis.

Conclusion

Although purulent pericarditis has become a rare diagnosis since the development of antibiotics, knowledge of how to identify it is essential since mortality reaches 100% if the diagnosis is missed.⁴ Even when the condition is promptly diagnosed and treated, mortality is 40%, mainly due to cardiac tamponade, septic shock, or constriction.¹ The case presented here illustrates the clinical features associated with this condition. Knowing these features can translate in a successful patient outcome.

Sjogren syndrome (SS) is a chronic inflammatory autoimmune disorder characterized by lymphocytic infiltration of lacrimal and salivary glands causing sicca syndrome.¹ The disease can extend beyond the exocrine glands, and systemic manifestations, including vasculitis, lung, renal or neurologic involvement, can occur.² Lung disease associated with SS is more commonly seen in women aged ≥ 60 years. The most common symptoms include dry cough, chest pain, and dyspnea on exertion. Sjogren syndrome also may produce several respiratory complications, including bronchial hyperresponsiveness, bronchiolitis, bronchiectasis, pulmonary infections, pulmonary amyloidosis, pulmonary embolism, pulmonary hypertension, lymphomas, and interstitial lung diseases (ILD).² Although ILD typically occurs 5 to 10 years after the onset of SS, lung disease can precede SS.

Pulmonary involvement is associated with systemic manifestations, hypergammaglobulinemia, and anti-SSA and anti-SSB antibodies.² Laboratory tests that confirm a diagnosis of SS include antinuclear antibody (ANA), anti-Ro/SSA, and anti-La/SSB antibodies.² Pulmonary function test (PFT) results appear to reflect impairment of either the lung (restrictive syndrome) or airways (obstructive syndrome).² Imaging abnormalities may include ground-glass attenuation, subpleural small nodules, nonseptal linear opacities, interlobular septal thickening, bronchiectasis, and cysts.³ Therefore, many ILD cases show similar imaging and pathologic findings; nevertheless, they have identifiable etiology that are not idiopathic.

Case Presentation

A 67-year-old man with a medical history of hypertension, peripheral vascular disease, and keratoconjunctivitis sicca (treated with eye drops) developed progressive shortness of breath, dyspnea on exertion, and weight loss (40 pounds) over the course of 6 months. A pulmonary function test showed a restrictive abnormality with decreased diffusing capacity of the lungs for carbon monoxide (eFigure available online at www.fedprac.com). A chest computed tomography (CT) scan showed the presence of significant thickening of the interlobular septi that was more pronounced in the subpleural regions of the lungs and lower lobes, which was consistent with usual interstitial pneumonia. A chest X-ray conducted 4 months prior showed no significant acute cardiopulmonary abnormalities (Figure 1). An open lung wedge biopsy revealed chronic organizing pneumonia with mild interstitial chronic inflammation, smooth muscle hypertrophy, and honeycomb changes consistent with usual interstitial pneumonia.

The patient had been diagnosed with idiopathic pulmonary fibrosis (IPF) by a private physician and started pirfenidone and oxygen therapy. Three months later the patient presented to the VA Caribbean Healthcare System in San Juan Puerto Rico when he developed an exacerbation of IPF. The patient reported having fever, chills, dry cough, night sweats, and marked shortness of breath. He was found hypoxemic (partial pressure of O₂ was 50 mm Hg) and required a venturi mask set to 50% fractioned of inspired O₂ to maintain a peripheral oxygen saturation around 90%. A chest X-ray showed decreased lung volume with bilateral interstitial and alveolar disease (Figure 2). Leukocytosis was present at 17×10^-3/µl. The chest CT scan showed interval worsening of diffuse ground-glass airspace opacities and worsening of interstitial opacities; there

was absence of pulmonary embolism (Figure 3). The patient was admitted to the intensive care unit with a diagnosis of hypoxemic respiratory failure due to suspected exacerbation of IPF vs pneumonia and was given broad spectrum IV antibiotics and oxygen therapy.

After careful clinical assessment (+ dry eyes) and radiographic pattern evaluation (diffuse bilateral interstitial and ground-glass opacities), the clinical diagnosis of IPF was queried after the patient’s rheumatologic workup came back positive for ANA and anti-Ro/SSA tests. Since the etiology of ILD was secondary to SS, pirfenidone was discontinued, and the patient was started on steroid therapy with subsequent marked clinical improvement. Parotid biopsy revealed the presence of inflammatory cells supporting the diagnosis of ILD associated to SS. The patient was discharged home on a tapering dose of steroids. Four months after therapy with steroids, a follow-up chest CT scan without contrast showed a chronic ILD with improved ground-glass opacities (Figure 4). The patient currently is in good health without oxygen supplementation.

Discussion

Diagnosis of SS is challenging, since it may mimic other conditions such as IPF. The most common type of SS-associated ILD is nonspecific interstitial pneumonia (NSIP), although usual interstitial pneumonia (UIP) can be visualized, as in this case study. Usual interstitial pneumonia

is a lung pathology diagnosis characterized by spatial heterogeneity (patchy parenchymal involvement with abrupt transition from normal to diseased lung), architectural distortion (honeycomb changes, which consists of enlarged airspaces embedded in fibrotic tissue lined by bronchiolar epithelium and often filled with mucin and inflammatory cells, obliterating the normal alveolar tissue), and temporal heterogeneity (due to the presence of fibroblastic foci, which are the site of ongoing injury, embedded in a background of scar tissue and honeycombing that is indicative of an old established lung injury).⁴

 

Diagnosing IPF cannot be solely based on a lung biopsy consistent with UIP. Appropriate diagnosis should consider the clinical presentation; PFT, laboratory findings (including rheumatologic workup), imaging (especially radiographic patterns), and biopsies. Moreover, the pathologic characteristic of IPF, which is UIP, can be found with other diseases, such as SS. Thus, it is important to make an accurate diagnosis to provide the appropriate treatment available. Patients with ILD associated with SS who have worsening symptoms, PFT, and radiographic abnormalities may be treated with oral prednisone (daily dose: 1 mg/kg).

Conclusion

This case highlights the importance of making an adequate diagnosis of ILD considering that available treatments differ for all possible etiologies other than IPF. This is a true clinical concern taking into account that many patients might be receiving inappropriate therapy for IPF diagnosis, as illustrated in the case study.

Sjogren syndrome (SS) is a chronic inflammatory autoimmune disorder characterized by lymphocytic infiltration of lacrimal and salivary glands causing sicca syndrome.¹ The disease can extend beyond the exocrine glands, and systemic manifestations, including vasculitis, lung, renal or neurologic involvement, can occur.² Lung disease associated with SS is more commonly seen in women aged ≥ 60 years. The most common symptoms include dry cough, chest pain, and dyspnea on exertion. Sjogren syndrome also may produce several respiratory complications, including bronchial hyperresponsiveness, bronchiolitis, bronchiectasis, pulmonary infections, pulmonary amyloidosis, pulmonary embolism, pulmonary hypertension, lymphomas, and interstitial lung diseases (ILD).² Although ILD typically occurs 5 to 10 years after the onset of SS, lung disease can precede SS.

Pulmonary involvement is associated with systemic manifestations, hypergammaglobulinemia, and anti-SSA and anti-SSB antibodies.² Laboratory tests that confirm a diagnosis of SS include antinuclear antibody (ANA), anti-Ro/SSA, and anti-La/SSB antibodies.² Pulmonary function test (PFT) results appear to reflect impairment of either the lung (restrictive syndrome) or airways (obstructive syndrome).² Imaging abnormalities may include ground-glass attenuation, subpleural small nodules, nonseptal linear opacities, interlobular septal thickening, bronchiectasis, and cysts.³ Therefore, many ILD cases show similar imaging and pathologic findings; nevertheless, they have identifiable etiology that are not idiopathic.

Case Presentation

A 67-year-old man with a medical history of hypertension, peripheral vascular disease, and keratoconjunctivitis sicca (treated with eye drops) developed progressive shortness of breath, dyspnea on exertion, and weight loss (40 pounds) over the course of 6 months. A pulmonary function test showed a restrictive abnormality with decreased diffusing capacity of the lungs for carbon monoxide (eFigure available online at www.fedprac.com). A chest computed tomography (CT) scan showed the presence of significant thickening of the interlobular septi that was more pronounced in the subpleural regions of the lungs and lower lobes, which was consistent with usual interstitial pneumonia. A chest X-ray conducted 4 months prior showed no significant acute cardiopulmonary abnormalities (Figure 1). An open lung wedge biopsy revealed chronic organizing pneumonia with mild interstitial chronic inflammation, smooth muscle hypertrophy, and honeycomb changes consistent with usual interstitial pneumonia.

The patient had been diagnosed with idiopathic pulmonary fibrosis (IPF) by a private physician and started pirfenidone and oxygen therapy. Three months later the patient presented to the VA Caribbean Healthcare System in San Juan Puerto Rico when he developed an exacerbation of IPF. The patient reported having fever, chills, dry cough, night sweats, and marked shortness of breath. He was found hypoxemic (partial pressure of O₂ was 50 mm Hg) and required a venturi mask set to 50% fractioned of inspired O₂ to maintain a peripheral oxygen saturation around 90%. A chest X-ray showed decreased lung volume with bilateral interstitial and alveolar disease (Figure 2). Leukocytosis was present at 17×10^-3/µl. The chest CT scan showed interval worsening of diffuse ground-glass airspace opacities and worsening of interstitial opacities; there

was absence of pulmonary embolism (Figure 3). The patient was admitted to the intensive care unit with a diagnosis of hypoxemic respiratory failure due to suspected exacerbation of IPF vs pneumonia and was given broad spectrum IV antibiotics and oxygen therapy.

After careful clinical assessment (+ dry eyes) and radiographic pattern evaluation (diffuse bilateral interstitial and ground-glass opacities), the clinical diagnosis of IPF was queried after the patient’s rheumatologic workup came back positive for ANA and anti-Ro/SSA tests. Since the etiology of ILD was secondary to SS, pirfenidone was discontinued, and the patient was started on steroid therapy with subsequent marked clinical improvement. Parotid biopsy revealed the presence of inflammatory cells supporting the diagnosis of ILD associated to SS. The patient was discharged home on a tapering dose of steroids. Four months after therapy with steroids, a follow-up chest CT scan without contrast showed a chronic ILD with improved ground-glass opacities (Figure 4). The patient currently is in good health without oxygen supplementation.

Discussion

Diagnosis of SS is challenging, since it may mimic other conditions such as IPF. The most common type of SS-associated ILD is nonspecific interstitial pneumonia (NSIP), although usual interstitial pneumonia (UIP) can be visualized, as in this case study. Usual interstitial pneumonia

is a lung pathology diagnosis characterized by spatial heterogeneity (patchy parenchymal involvement with abrupt transition from normal to diseased lung), architectural distortion (honeycomb changes, which consists of enlarged airspaces embedded in fibrotic tissue lined by bronchiolar epithelium and often filled with mucin and inflammatory cells, obliterating the normal alveolar tissue), and temporal heterogeneity (due to the presence of fibroblastic foci, which are the site of ongoing injury, embedded in a background of scar tissue and honeycombing that is indicative of an old established lung injury).⁴

 

Diagnosing IPF cannot be solely based on a lung biopsy consistent with UIP. Appropriate diagnosis should consider the clinical presentation; PFT, laboratory findings (including rheumatologic workup), imaging (especially radiographic patterns), and biopsies. Moreover, the pathologic characteristic of IPF, which is UIP, can be found with other diseases, such as SS. Thus, it is important to make an accurate diagnosis to provide the appropriate treatment available. Patients with ILD associated with SS who have worsening symptoms, PFT, and radiographic abnormalities may be treated with oral prednisone (daily dose: 1 mg/kg).

Conclusion

This case highlights the importance of making an adequate diagnosis of ILD considering that available treatments differ for all possible etiologies other than IPF. This is a true clinical concern taking into account that many patients might be receiving inappropriate therapy for IPF diagnosis, as illustrated in the case study.

Sjogren syndrome (SS) is a chronic inflammatory autoimmune disorder characterized by lymphocytic infiltration of lacrimal and salivary glands causing sicca syndrome.¹ The disease can extend beyond the exocrine glands, and systemic manifestations, including vasculitis, lung, renal or neurologic involvement, can occur.² Lung disease associated with SS is more commonly seen in women aged ≥ 60 years. The most common symptoms include dry cough, chest pain, and dyspnea on exertion. Sjogren syndrome also may produce several respiratory complications, including bronchial hyperresponsiveness, bronchiolitis, bronchiectasis, pulmonary infections, pulmonary amyloidosis, pulmonary embolism, pulmonary hypertension, lymphomas, and interstitial lung diseases (ILD).² Although ILD typically occurs 5 to 10 years after the onset of SS, lung disease can precede SS.

Pulmonary involvement is associated with systemic manifestations, hypergammaglobulinemia, and anti-SSA and anti-SSB antibodies.² Laboratory tests that confirm a diagnosis of SS include antinuclear antibody (ANA), anti-Ro/SSA, and anti-La/SSB antibodies.² Pulmonary function test (PFT) results appear to reflect impairment of either the lung (restrictive syndrome) or airways (obstructive syndrome).² Imaging abnormalities may include ground-glass attenuation, subpleural small nodules, nonseptal linear opacities, interlobular septal thickening, bronchiectasis, and cysts.³ Therefore, many ILD cases show similar imaging and pathologic findings; nevertheless, they have identifiable etiology that are not idiopathic.

Case Presentation

A 67-year-old man with a medical history of hypertension, peripheral vascular disease, and keratoconjunctivitis sicca (treated with eye drops) developed progressive shortness of breath, dyspnea on exertion, and weight loss (40 pounds) over the course of 6 months. A pulmonary function test showed a restrictive abnormality with decreased diffusing capacity of the lungs for carbon monoxide (eFigure available online at www.fedprac.com). A chest computed tomography (CT) scan showed the presence of significant thickening of the interlobular septi that was more pronounced in the subpleural regions of the lungs and lower lobes, which was consistent with usual interstitial pneumonia. A chest X-ray conducted 4 months prior showed no significant acute cardiopulmonary abnormalities (Figure 1). An open lung wedge biopsy revealed chronic organizing pneumonia with mild interstitial chronic inflammation, smooth muscle hypertrophy, and honeycomb changes consistent with usual interstitial pneumonia.

The patient had been diagnosed with idiopathic pulmonary fibrosis (IPF) by a private physician and started pirfenidone and oxygen therapy. Three months later the patient presented to the VA Caribbean Healthcare System in San Juan Puerto Rico when he developed an exacerbation of IPF. The patient reported having fever, chills, dry cough, night sweats, and marked shortness of breath. He was found hypoxemic (partial pressure of O₂ was 50 mm Hg) and required a venturi mask set to 50% fractioned of inspired O₂ to maintain a peripheral oxygen saturation around 90%. A chest X-ray showed decreased lung volume with bilateral interstitial and alveolar disease (Figure 2). Leukocytosis was present at 17×10^-3/µl. The chest CT scan showed interval worsening of diffuse ground-glass airspace opacities and worsening of interstitial opacities; there

was absence of pulmonary embolism (Figure 3). The patient was admitted to the intensive care unit with a diagnosis of hypoxemic respiratory failure due to suspected exacerbation of IPF vs pneumonia and was given broad spectrum IV antibiotics and oxygen therapy.

After careful clinical assessment (+ dry eyes) and radiographic pattern evaluation (diffuse bilateral interstitial and ground-glass opacities), the clinical diagnosis of IPF was queried after the patient’s rheumatologic workup came back positive for ANA and anti-Ro/SSA tests. Since the etiology of ILD was secondary to SS, pirfenidone was discontinued, and the patient was started on steroid therapy with subsequent marked clinical improvement. Parotid biopsy revealed the presence of inflammatory cells supporting the diagnosis of ILD associated to SS. The patient was discharged home on a tapering dose of steroids. Four months after therapy with steroids, a follow-up chest CT scan without contrast showed a chronic ILD with improved ground-glass opacities (Figure 4). The patient currently is in good health without oxygen supplementation.

Discussion

Diagnosis of SS is challenging, since it may mimic other conditions such as IPF. The most common type of SS-associated ILD is nonspecific interstitial pneumonia (NSIP), although usual interstitial pneumonia (UIP) can be visualized, as in this case study. Usual interstitial pneumonia

is a lung pathology diagnosis characterized by spatial heterogeneity (patchy parenchymal involvement with abrupt transition from normal to diseased lung), architectural distortion (honeycomb changes, which consists of enlarged airspaces embedded in fibrotic tissue lined by bronchiolar epithelium and often filled with mucin and inflammatory cells, obliterating the normal alveolar tissue), and temporal heterogeneity (due to the presence of fibroblastic foci, which are the site of ongoing injury, embedded in a background of scar tissue and honeycombing that is indicative of an old established lung injury).⁴

 

Diagnosing IPF cannot be solely based on a lung biopsy consistent with UIP. Appropriate diagnosis should consider the clinical presentation; PFT, laboratory findings (including rheumatologic workup), imaging (especially radiographic patterns), and biopsies. Moreover, the pathologic characteristic of IPF, which is UIP, can be found with other diseases, such as SS. Thus, it is important to make an accurate diagnosis to provide the appropriate treatment available. Patients with ILD associated with SS who have worsening symptoms, PFT, and radiographic abnormalities may be treated with oral prednisone (daily dose: 1 mg/kg).

Conclusion

This case highlights the importance of making an adequate diagnosis of ILD considering that available treatments differ for all possible etiologies other than IPF. This is a true clinical concern taking into account that many patients might be receiving inappropriate therapy for IPF diagnosis, as illustrated in the case study.