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A forty-year old man with advanced acquired immune deficiency syndrome and bilateral pulmonary infiltrates
Respiratory Medicine CME 4 (2011) 184e186
Contents lists available at ScienceDirect
Respiratory Medicine CME journal homepage: www.elsevier.com/locate/rmedc
Case Report
A forty-year old man with advanced acquired immune deficiency syndrome and bilateral pulmonary infiltrates Ikjot Kaur a, Agustina Saenz a, *, Harish Iyer a, b, Glenn Eiger a, c, Robert Fischer d, Vladimir Zagrebelsky e a
Department of Medicine, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA Department of Gastroenterology, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA c Department of Pulmonary Critical Care, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA d Department of Infectious Diseases, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA e Department of Geriatrics, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 February 2011 Accepted 24 March 2011
This report describes a 40-year old man with a history of acquired immunodeficiency syndrome (AIDS) diagnosed with Pneumocystis jiroveci pneumonia (PJP) twice prior to this admission, who presented with 3 days of fever, non-productive cough and shortness of breath. The patient was treated empirically for PJP, but his condition deteriorated rapidly and he expired despite resuscitative efforts. The bronchoalveolar lavage (BAL) and blood cultures grew Cryptococcus neoformans. Very few cases of disseminated cryptococcosis presenting as acute respiratory failure have been reported. Cryptococcosis is a common opportunistic infection that should be considered in patients with AIDS presenting with bilateral pulmonary infiltrates and fever. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Disseminated cryptococcosis Pneumocystis jiroveci pneumonia Acute respiratory failure Acquired immunodeficiency syndrome Opportunistic infection
1. Case report
Key points Serum CrAg (sCrAg) is a rapid and reliable method of diagnosing cryptococcal infection, with sensitivity and specificity between 93 and 100% depending on the kit used. Chest radiographic findings in pulmonary cryptococcosis can be similar to those in PJP, ranging from diffuse infiltrates to solitary nodules, focal consolidation, hilar lymphadenopathy, cavities and pleural effusion. Amphotericin B plus flucytosine for 2 weeks, followed by fluconazole for 8e10 weeks of consolidation therapy and then life-long maintenance therapy, is recommended as first-line therapy.
* Corresponding author. Tel.: þ1 215 317 4833. E-mail addresses: [email protected] (I. Kaur), [email protected] (A. Saenz), [email protected] (H. Iyer), [email protected] (G. Eiger), fischerr@ einstein.edu (R. Fischer), [email protected] (V. Zagrebelsky). 1755-0017/$36.00 Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmedc.2011.03.004
A 40-year old man was admitted to the hospital with 3 days of fever, non-productive cough and shortness of breath. The patient denied headache or blurry vision. He had AIDS and his last CD4 count was twelve. He was not on anti-retroviral therapy because of non-compliance. 18 and 4 months prior to admission he had Pneumocystis jiroveci pneumonia (PJP) diagnosed by bronchoalveolar lavage (BAL); both episodes were treated with trimethoprimsulfamethoxazole (TMP-SMZ) and prednisone. One week after his last discharge he was readmitted with agranulocytosis secondary to TMP-SMZ, which was discontinued, and he was switched to primaquine and clindamycin. Unfortunately, he was non-compliant with this regimen. Examination on admission revealed blood pressure (BP) 116/89, heart rate 111 beats per minute, temperature 36.9 C, respiratory rate 26, transcutaneous oxygen saturation 91% on room air and 94% on 4-L/min oxygen via nasal cannula. There was no jugular venous distention, lymphadenopathy, cyanosis, clubbing, pallor or icterus. Bibasilar coarse crackles were heard on chest exam. Cardiac exam was unremarkable except for tachycardia. The abdomen was soft with no organomegaly. Neurologic exam was unremarkable. Laboratory findings included white blood cell count 3.7 109/L, hemoglobin 17 g/dL, platelets 276 109/L. BUN was 33 mg/dL creatinine 1.7 mg/dL (baseline 1.1 mg/dL), sodium 133 mmol/L, potassium 5 mmol/L, chloride 97 mmol/L, bicarbonate 19 mmol/L,
I. Kaur et al. / Respiratory Medicine CME 4 (2011) 184e186
anion gap 15. Arterial blood gas analysis on nasal cannula 4-L oxygen showed pH 7.38, PaCO2 26 mmHg, PaO2 94 mmHg. EKG revealed sinus tachycardia at rate of 111. Chest X ray (CXR) is shown below. He was treated for presumed PJP with clindamycin, primaquine and prednisone. Over the next 24e36 h, he became more tachypneic with increasing oxygen requirements. He remained hypoxic despite receiving oxygen delivered through a non-rebreather mask. A repeat CXR was unchanged. He was intubated and ventilated, and a BAL was performed. The metabolic acidosis worsened and he died despite resuscitative attempts. Culture of BAL fluid grew Cryptococcus neoformans. No PJP was identified in the BAL. Subsequently, the previously collected blood cultures also grew C. neoformans.
2. Discussion Despite the advent of anti-retroviral therapy, PJP remains one of the most common opportunistic AIDS-related pulmonary infections. Although some controversies exist regarding diagnosis and management of PJP, experience and data now support empiric treatment of PJP in a subset of carefully selected patients, with BAL performed in case of clinical deterioration or failure to show improvement within 4e5 days. The typical radiological features of PJP are bilateral, symmetrical pulmonary infiltrates emanating from the hilar regions. However, while empirically treating PJP it is important to realize that the radiological presentation can be mimicked by other opportunistic infections including cryptococcosis, tuberculosis, and non-infectious diseases including interstitial pneumonia, lymphoma, Kaposi sarcoma, and alveolar hemorrhage. Coinfection with PJP and C. neoformans has been demonstrated by various studies in up to 30% of autopsies performed in HIV-infected patients. Our patient fulfilled the CDC criteria for presumptive diagnosis of PJP and was initially managed empirically, but had a deteriorating course with a postmortem diagnosis of disseminated cryptococcosis. Cryptococcosis, a possibly under-diagnosed opportunistic infection in AIDS patients, is caused by an encapsulated yeast, C. neoformans, commonly acquired from inhalation of the pathogen, though in some cases skin has also been shown to be a portal of entry. It is postulated that the organism can remain dormant in the lungs or the central nervous system and that cryptococcosis in AIDS patients represents reactivation of a latent infection. The most frequent manifestation of cryptococcosis in an AIDS patient is subacute meningitis or meningoencephalitis, generally with a CD4 count less than 100. Pulmonary cryptococcosis is asymptomatic in up to one third of non-HIV patients whereas most HIV positive patients are symptomatic with non-specific symptoms. The most common symptom associated with pulmonary cryptococcsis in an HIV positive patient is cough in 71e94%; other symptoms include dyspnea, fever, weight loss, headache chest pain, and hemoptysis.1 Dissemination is defined as isolation of Cryptococcus from an extrapulmonary site such as blood or cerebrospinal fluid. Central nervous system (CNS) involvement is seen at the time of diagnosis of pulmonary cryptococcosis in 22e92% of cases.1 A recent study seeking to identify markers of disseminated infection in pulmonary cryptococcosis found fever, interstitial pulmonary abnormalities and pleural effusions more frequently associated with disseminated disease and highest titers of serum cryptococcal antigen.2 Disseminated cryptococcosis presenting as acute respiratory failure (as in our case) is an uncommon presentation and has been described mainly in a few reports. In the largest reported case series of patients with AIDS and cryptococcal disease, acute respiratory failure occurred in 13.8% (29/210) of cases, with a 48 h mortality of 100%. Elevated LDH levels, interstitial pulmonary infiltrates and
185
cutaneous lesions suggested disseminated disease in this group of patients.3 Diagnosis of cryptococcosis is made by isolation of Cryptococcus from a sterile body site, by histopathologic analysis, or by detection of cryptococcal capsular antigen (CrAg). Serum CrAg (sCrAg) is a rapid and reliable method of diagnosing cryptococcal infection, with sensitivity and specificity between 93 and 100% depending on the kit used.4 In AIDS patients localized pulmonary cryptococcosis is generally associated with a negative sCrAg, hence its presence in serum especially in high titers may be an indicator of dissemination and should prompt further evaluation by means of a lumbar puncture to look for CNS invasion. As stated previously, chest radiographic findings in pulmonary cryptococcosis can be similar to those in PJP, ranging from diffuse infiltrates to solitary nodules, focal consolidation, hilar lymphadenopathy, cavities and pleural effusion. The rationale for treatment of isolated pulmonary cryptococcosis stems from studies, which have shown that these patients are at high risk of dissemination. Isolated pulmonary cryptococcosis with negative cerebrospinal fluid (CSF) CrAg and cultures can be treated with azoles (fluconazole) if symptoms are mild or moderate. There are no controlled trials for management of pulmonary cryptococcosis, but early therapy of non-CNS pulmonary and extrapulmonary disease in AIDS patients reduces the risk of progression to potentially life-threatening CNS disease. Detection of a positive sCrAg mandates a workup for dissemination including blood cultures and lumbar puncture to exclude CNS involvement. For disseminated cryptococcosis treatment guidelines lean towards treating with the same regimen as for cryptococcal meningitis. Based on the results of the MSG/ACTG clinical trial, amphotericin B plus flucytosine for 2 weeks, followed by fluconazole for 8e10 weeks of consolidation therapy and then lifelong maintenance therapy, is recommended as first-line therapy.4,5 Consider stopping maintenance fluconazole after 1 year of treatment during anti-retroviral therapy in patients with a CD4 count higher than 100 cells/microL, very low or undetectable HIV RNA level, sustained for more than 3 months and Cryptococcal antigen titer less than 1:512.5 Given the relatively non-specific clinical signs and symptoms, variable radiographic signs, and higher incidence of other pulmonary opportunistic infections such as PJP, it is likely that pulmonary cryptococcosis is an under-diagnosed entity and not recognized until dissemination. In an autopsy series performed on 42 AIDS patients, an unsuspected disease was found in 18, with disseminated cryptococcal infection accounting for 28% of diagnoses (5/18). In all those cases PJP was considered the cause of the patient’s illness.6 Returning to our patient, he was started on empiric therapy for PJP based on a consistent clinical picture, without establishing a definitive diagnosis. Because of the potentially grave consequences of overlooking disseminated cryptococcosis, we believe every patient who is empirically treated for PJP should have a sCrAg performed. This presentation reveals the importance of considering C. neoformans as a potential organism in patients with AIDS and hypoxia with bilateral interstitial pulmonary infiltrates. Serum cryptococcal antigen is a rapid test with very high sensitivity and specificity, and can be used as a reliable method to exclude this potentially fatal disease. Conflict of interest The paper is not under review, or published previously. There is no conflict of interest for any of the authors. All the authorship is aware of and approves the manuscript being submitted to this journal.
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I. Kaur et al. / Respiratory Medicine CME 4 (2011) 184e186
References 1. Lortholary O, Nunez H, Brauner MW, et al. Pulmonary cryptococcosis. Semin Respir Crit Care Med 2004;25(2):145e57. 2. Hung MS, Tsai YH, Lee CH, et al. Pulmonary cryptococcosis: clinical, radiographical and serological markers of dissemination. Respirology 2008;13(2):247e51. 3. Visnegarwala F, Graviss EA, Lacke CE, et al. Acute respiratory failure associated with cryptococcosis in patients with AIDS: análisis of predictive factors. Clin Infect Dis 1998;27:1231e7.
4. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000;30:710e8. 5. Perfect J, Dismukes W, Dromer F, et al. Clinical practice guidelines for the managment of cryptococcal disease: 2010 update by the infectious disease society of America. Clin Infect Dis 2010;50. 6. Bernicker EH, Atmar RL, Schaffner DL, et al. Unanticipated diagnoses found at autopsy in an urban public teaching hospital. Am J Med Sci 1996;311 (5):215e20.
Contents lists available at ScienceDirect
Respiratory Medicine CME journal homepage: www.elsevier.com/locate/rmedc
Case Report
A forty-year old man with advanced acquired immune deficiency syndrome and bilateral pulmonary infiltrates Ikjot Kaur a, Agustina Saenz a, *, Harish Iyer a, b, Glenn Eiger a, c, Robert Fischer d, Vladimir Zagrebelsky e a
Department of Medicine, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA Department of Gastroenterology, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA c Department of Pulmonary Critical Care, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA d Department of Infectious Diseases, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA e Department of Geriatrics, Albert Einstein Medical Center, 5501 Old York Road, Philadelphia, PA 19141, USA b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 15 February 2011 Accepted 24 March 2011
This report describes a 40-year old man with a history of acquired immunodeficiency syndrome (AIDS) diagnosed with Pneumocystis jiroveci pneumonia (PJP) twice prior to this admission, who presented with 3 days of fever, non-productive cough and shortness of breath. The patient was treated empirically for PJP, but his condition deteriorated rapidly and he expired despite resuscitative efforts. The bronchoalveolar lavage (BAL) and blood cultures grew Cryptococcus neoformans. Very few cases of disseminated cryptococcosis presenting as acute respiratory failure have been reported. Cryptococcosis is a common opportunistic infection that should be considered in patients with AIDS presenting with bilateral pulmonary infiltrates and fever. Ó 2011 Elsevier Ltd. All rights reserved.
Keywords: Disseminated cryptococcosis Pneumocystis jiroveci pneumonia Acute respiratory failure Acquired immunodeficiency syndrome Opportunistic infection
1. Case report
Key points Serum CrAg (sCrAg) is a rapid and reliable method of diagnosing cryptococcal infection, with sensitivity and specificity between 93 and 100% depending on the kit used. Chest radiographic findings in pulmonary cryptococcosis can be similar to those in PJP, ranging from diffuse infiltrates to solitary nodules, focal consolidation, hilar lymphadenopathy, cavities and pleural effusion. Amphotericin B plus flucytosine for 2 weeks, followed by fluconazole for 8e10 weeks of consolidation therapy and then life-long maintenance therapy, is recommended as first-line therapy.
* Corresponding author. Tel.: þ1 215 317 4833. E-mail addresses: [email protected] (I. Kaur), [email protected] (A. Saenz), [email protected] (H. Iyer), [email protected] (G. Eiger), fischerr@ einstein.edu (R. Fischer), [email protected] (V. Zagrebelsky). 1755-0017/$36.00 Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.rmedc.2011.03.004
A 40-year old man was admitted to the hospital with 3 days of fever, non-productive cough and shortness of breath. The patient denied headache or blurry vision. He had AIDS and his last CD4 count was twelve. He was not on anti-retroviral therapy because of non-compliance. 18 and 4 months prior to admission he had Pneumocystis jiroveci pneumonia (PJP) diagnosed by bronchoalveolar lavage (BAL); both episodes were treated with trimethoprimsulfamethoxazole (TMP-SMZ) and prednisone. One week after his last discharge he was readmitted with agranulocytosis secondary to TMP-SMZ, which was discontinued, and he was switched to primaquine and clindamycin. Unfortunately, he was non-compliant with this regimen. Examination on admission revealed blood pressure (BP) 116/89, heart rate 111 beats per minute, temperature 36.9 C, respiratory rate 26, transcutaneous oxygen saturation 91% on room air and 94% on 4-L/min oxygen via nasal cannula. There was no jugular venous distention, lymphadenopathy, cyanosis, clubbing, pallor or icterus. Bibasilar coarse crackles were heard on chest exam. Cardiac exam was unremarkable except for tachycardia. The abdomen was soft with no organomegaly. Neurologic exam was unremarkable. Laboratory findings included white blood cell count 3.7 109/L, hemoglobin 17 g/dL, platelets 276 109/L. BUN was 33 mg/dL creatinine 1.7 mg/dL (baseline 1.1 mg/dL), sodium 133 mmol/L, potassium 5 mmol/L, chloride 97 mmol/L, bicarbonate 19 mmol/L,
I. Kaur et al. / Respiratory Medicine CME 4 (2011) 184e186
anion gap 15. Arterial blood gas analysis on nasal cannula 4-L oxygen showed pH 7.38, PaCO2 26 mmHg, PaO2 94 mmHg. EKG revealed sinus tachycardia at rate of 111. Chest X ray (CXR) is shown below. He was treated for presumed PJP with clindamycin, primaquine and prednisone. Over the next 24e36 h, he became more tachypneic with increasing oxygen requirements. He remained hypoxic despite receiving oxygen delivered through a non-rebreather mask. A repeat CXR was unchanged. He was intubated and ventilated, and a BAL was performed. The metabolic acidosis worsened and he died despite resuscitative attempts. Culture of BAL fluid grew Cryptococcus neoformans. No PJP was identified in the BAL. Subsequently, the previously collected blood cultures also grew C. neoformans.
2. Discussion Despite the advent of anti-retroviral therapy, PJP remains one of the most common opportunistic AIDS-related pulmonary infections. Although some controversies exist regarding diagnosis and management of PJP, experience and data now support empiric treatment of PJP in a subset of carefully selected patients, with BAL performed in case of clinical deterioration or failure to show improvement within 4e5 days. The typical radiological features of PJP are bilateral, symmetrical pulmonary infiltrates emanating from the hilar regions. However, while empirically treating PJP it is important to realize that the radiological presentation can be mimicked by other opportunistic infections including cryptococcosis, tuberculosis, and non-infectious diseases including interstitial pneumonia, lymphoma, Kaposi sarcoma, and alveolar hemorrhage. Coinfection with PJP and C. neoformans has been demonstrated by various studies in up to 30% of autopsies performed in HIV-infected patients. Our patient fulfilled the CDC criteria for presumptive diagnosis of PJP and was initially managed empirically, but had a deteriorating course with a postmortem diagnosis of disseminated cryptococcosis. Cryptococcosis, a possibly under-diagnosed opportunistic infection in AIDS patients, is caused by an encapsulated yeast, C. neoformans, commonly acquired from inhalation of the pathogen, though in some cases skin has also been shown to be a portal of entry. It is postulated that the organism can remain dormant in the lungs or the central nervous system and that cryptococcosis in AIDS patients represents reactivation of a latent infection. The most frequent manifestation of cryptococcosis in an AIDS patient is subacute meningitis or meningoencephalitis, generally with a CD4 count less than 100. Pulmonary cryptococcosis is asymptomatic in up to one third of non-HIV patients whereas most HIV positive patients are symptomatic with non-specific symptoms. The most common symptom associated with pulmonary cryptococcsis in an HIV positive patient is cough in 71e94%; other symptoms include dyspnea, fever, weight loss, headache chest pain, and hemoptysis.1 Dissemination is defined as isolation of Cryptococcus from an extrapulmonary site such as blood or cerebrospinal fluid. Central nervous system (CNS) involvement is seen at the time of diagnosis of pulmonary cryptococcosis in 22e92% of cases.1 A recent study seeking to identify markers of disseminated infection in pulmonary cryptococcosis found fever, interstitial pulmonary abnormalities and pleural effusions more frequently associated with disseminated disease and highest titers of serum cryptococcal antigen.2 Disseminated cryptococcosis presenting as acute respiratory failure (as in our case) is an uncommon presentation and has been described mainly in a few reports. In the largest reported case series of patients with AIDS and cryptococcal disease, acute respiratory failure occurred in 13.8% (29/210) of cases, with a 48 h mortality of 100%. Elevated LDH levels, interstitial pulmonary infiltrates and
185
cutaneous lesions suggested disseminated disease in this group of patients.3 Diagnosis of cryptococcosis is made by isolation of Cryptococcus from a sterile body site, by histopathologic analysis, or by detection of cryptococcal capsular antigen (CrAg). Serum CrAg (sCrAg) is a rapid and reliable method of diagnosing cryptococcal infection, with sensitivity and specificity between 93 and 100% depending on the kit used.4 In AIDS patients localized pulmonary cryptococcosis is generally associated with a negative sCrAg, hence its presence in serum especially in high titers may be an indicator of dissemination and should prompt further evaluation by means of a lumbar puncture to look for CNS invasion. As stated previously, chest radiographic findings in pulmonary cryptococcosis can be similar to those in PJP, ranging from diffuse infiltrates to solitary nodules, focal consolidation, hilar lymphadenopathy, cavities and pleural effusion. The rationale for treatment of isolated pulmonary cryptococcosis stems from studies, which have shown that these patients are at high risk of dissemination. Isolated pulmonary cryptococcosis with negative cerebrospinal fluid (CSF) CrAg and cultures can be treated with azoles (fluconazole) if symptoms are mild or moderate. There are no controlled trials for management of pulmonary cryptococcosis, but early therapy of non-CNS pulmonary and extrapulmonary disease in AIDS patients reduces the risk of progression to potentially life-threatening CNS disease. Detection of a positive sCrAg mandates a workup for dissemination including blood cultures and lumbar puncture to exclude CNS involvement. For disseminated cryptococcosis treatment guidelines lean towards treating with the same regimen as for cryptococcal meningitis. Based on the results of the MSG/ACTG clinical trial, amphotericin B plus flucytosine for 2 weeks, followed by fluconazole for 8e10 weeks of consolidation therapy and then lifelong maintenance therapy, is recommended as first-line therapy.4,5 Consider stopping maintenance fluconazole after 1 year of treatment during anti-retroviral therapy in patients with a CD4 count higher than 100 cells/microL, very low or undetectable HIV RNA level, sustained for more than 3 months and Cryptococcal antigen titer less than 1:512.5 Given the relatively non-specific clinical signs and symptoms, variable radiographic signs, and higher incidence of other pulmonary opportunistic infections such as PJP, it is likely that pulmonary cryptococcosis is an under-diagnosed entity and not recognized until dissemination. In an autopsy series performed on 42 AIDS patients, an unsuspected disease was found in 18, with disseminated cryptococcal infection accounting for 28% of diagnoses (5/18). In all those cases PJP was considered the cause of the patient’s illness.6 Returning to our patient, he was started on empiric therapy for PJP based on a consistent clinical picture, without establishing a definitive diagnosis. Because of the potentially grave consequences of overlooking disseminated cryptococcosis, we believe every patient who is empirically treated for PJP should have a sCrAg performed. This presentation reveals the importance of considering C. neoformans as a potential organism in patients with AIDS and hypoxia with bilateral interstitial pulmonary infiltrates. Serum cryptococcal antigen is a rapid test with very high sensitivity and specificity, and can be used as a reliable method to exclude this potentially fatal disease. Conflict of interest The paper is not under review, or published previously. There is no conflict of interest for any of the authors. All the authorship is aware of and approves the manuscript being submitted to this journal.
186
I. Kaur et al. / Respiratory Medicine CME 4 (2011) 184e186
References 1. Lortholary O, Nunez H, Brauner MW, et al. Pulmonary cryptococcosis. Semin Respir Crit Care Med 2004;25(2):145e57. 2. Hung MS, Tsai YH, Lee CH, et al. Pulmonary cryptococcosis: clinical, radiographical and serological markers of dissemination. Respirology 2008;13(2):247e51. 3. Visnegarwala F, Graviss EA, Lacke CE, et al. Acute respiratory failure associated with cryptococcosis in patients with AIDS: análisis of predictive factors. Clin Infect Dis 1998;27:1231e7.
4. Saag MS, Graybill RJ, Larsen RA, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis 2000;30:710e8. 5. Perfect J, Dismukes W, Dromer F, et al. Clinical practice guidelines for the managment of cryptococcal disease: 2010 update by the infectious disease society of America. Clin Infect Dis 2010;50. 6. Bernicker EH, Atmar RL, Schaffner DL, et al. Unanticipated diagnoses found at autopsy in an urban public teaching hospital. Am J Med Sci 1996;311 (5):215e20.