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A Case of Cryptogenic Dyspnea: Disseminated Cryptococcosis

      Presentation

      A week of flu-like symptoms was the prelude to a catastrophic course for a 38-year-old African American woman, who had seemed to be in generally good health. She presented with a 2-day history of dyspnea and pleuritic chest pain. Initially, the dyspnea was present only with exertion, but it progressed rapidly to shortness of breath at rest. During the week prior to admission, she also had myalgias, fatigue, sore throat, headache, and a cough that produced yellow sputum.
      The patient was unaware of any recent sick contacts and had no history of travel or immobilization. Her medical history included hypertension and asthma, and she was being treated with amlodipine, valsartan, montelukast, and an albuterol inhaler. She was engaged to be married, had 2 children, aged 4 years and 9 years, and denied use of tobacco, illicit drugs, and alcohol. She also reported that 6 months earlier, she had undergone human immunodeficiency virus (HIV) testing, which produced negative results.

      Assessment

      The patient appeared ill, with increased work of breathing. She had a temperature of 101.5° F (38.6° C), a blood pressure of 90/64 mm Hg, a heart rate of 112 beats per minute, and a respiratory rate of 26 breaths per minute. Her oxygen saturation was 86% on room air. A cardiac examination demonstrated a regular tachycardia with a loud second heart sound but no murmurs, rubs or gallops. Her lungs were clear to auscultation, bilaterally. Jugular venous pressure was measured at 16 cm of water. Her abdomen was soft, nontender, and nondistended without hepatosplenomegaly. She had trace pedal edema and no rash. Pulses were 2+ in all 4 extremities, and all extremities were well perfused. No neurologic deficits were detected.
      The patient's white blood cell count was 2.7 x 103 cells/μL with 49% neutrophils, 38% lymphocytes, 9% monocytes, and 1% eosinophils. Her hemoglobin was 12.7 g/dL, and her platelet count was 237,000 cells/μL. Other laboratory values were as follows: total protein, 7.1 g/dL; albumin, 2.6 g/dL; creatine kinase, 190 U/L; and initial troponin I level, 0.771 ng/mL. Aspartate aminotransferase and alanine aminotransferase levels were mildly elevated. Electrocardiography showed sinus tachycardia with T wave inversions in leads III, aVF, V3, and V4, an S wave in lead I, and a small Q wave in lead III (Figure 1). A chest radiograph revealed prominent pulmonary vasculature (Figure 2).
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      Figure 1Electrocardiography showed sinus tachycardia with nonspecific T wave inversions, an S wave in lead I, and a small Q wave in lead III.
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      Figure 2A chest radiograph revealed prominent pulmonary vasculature.
      Computed tomography (CT) angiography of the chest with intravenous contrast did not show central pulmonary embolism, but there was suboptimal opacification of the subsegmental pulmonary arteries. Mild scattered atelectasis and fibrotic changes were seen in the lungs. An 8-mm pulmonary nodule in the medial aspect of the right middle lobe was noted, along with mild mediastinal, bilateral hilar, and right paratracheal adenopathy. A ventilation perfusion scan of the lungs was interpreted as low probability for pulmonary embolism.
      Subsequent transthoracic echocardiography showed a small left ventricle with an ejection fraction of 65-70%. The right ventricle was moderately dilated and mildly hypertrophic with severely reduced function. A flattened interventricular septum was evident, as was akinesis of the right ventricular free wall's midsegment. The right ventricular apex functioned normally. Moderate tricuspid regurgitation was present, and the pulmonary artery systolic pressure was estimated at 70 mm Hg (Figure 3). Right heart catheterization demonstrated a pulmonary artery pressure of 52/30 mm Hg with a mean pressure of 37 mm Hg. Pulmonary capillary wedge pressure was 10 mm Hg, and pulmonary artery hemoglobin saturation was 31%. Cardiac output by thermodilution was 3.5 L/min with a corresponding cardiac index of 1.52 L/min/m2.
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      Figure 3Transthoracic echocardiography in the parasternal short-axis view disclosed right ventricular dilatation and a flattened intraventricular “D-shaped” septum consistent with right ventricular pressure overload.

      Diagnosis

      The patient was in profound shock, as demonstrated by her vital signs and low cardiac output. Shock can be distributive, obstructive, cardiogenic, or hypovolemic. While distributive shock is triggered by septic, anaphylactic, neurogenic, or endocrine sources, obstructive shock is due to blockage of the great vessels, classically via cardiac tamponade, pulmonary embolism, tension pneumothorax, or critical aortic stenosis. Cardiogenic shock is caused by pump failure, typically spurred by myocardial infarction, myocarditis, toxins, valvulopathy, or arrhythmia. Hypovolemic shock results from insufficient circulatory volume attributable to fluid loss from vomiting, diarrhea, burns, or bleeding. Echocardiographic findings of right heart failure, pulmonary hypertension, and normal left ventricular end-diastolic pressure indicated that the etiology of shock in our patient's case was likely to be acute cor pulmonale.
      Massive pulmonary embolism and acute respiratory distress syndrome are the most common causes of acute cor pulmonale. In acute respiratory distress syndrome, hypoxia-induced vasoconstriction, microthrombus formation, and interstitial edema cause pulmonary hypertension. Increased blood viscosity also may play a role. However, our patient's imaging results did not support a diagnosis of acute respiratory distress syndrome, since the typical chest x-ray and CT findings were absent. Similarly, classic pulmonary embolism from a deep vein thrombosis was essentially ruled out, given the negative CT angiography and low probability ventilation perfusion scan. At that point, it was believed that the patient's symptoms might have been induced by an entity that caused increased blood viscosity or pulmonary microvascular occlusion; one that could not be seen on imaging studies.

      Management

      Broad spectrum antibiotics were started; specifically, vancomycin and piperacillin-tazobactam. Trimethoprim-sulfamethoxazole also was initiated, since concern for Pneumocystis jirovecii pneumonia was prompted by the CT results, leukopenia, and protein albumin dissociation. Nonetheless, the patient's respiratory status progressively worsened, requiring intubation and mechanical ventilation. Vasopressors were administered when her blood pressure remained low and unresponsive to fluid resuscitation. She developed pulseless electrical activity, and cardiac resuscitation was attempted for 80 minutes. During this period, she also received intravenous tissue plasminogen activator and inhaled nitrous oxide. Unfortunately, all efforts to save the patient were unsuccessful, and she died less than 17 hours after her initial presentation.
      A post-mortem HIV quantitative polymerase chain reaction detected 104,788 copies of viral RNA. Peripheral blood cultures grew 2 out of 2 bottles of Cryptococcus neoformans. Autopsy revealed disseminated cryptococcal infection with organisms isolated from the pulmonary vasculature, lung parenchyma and lymph nodes, myocardial tissue, leptomeninges, spleen, thyroid gland, and palatine tonsils (Figures 4 and 5). The right ventricle was enlarged and mildly hypertrophied. Diffuse hilar and mediastinal lymphadenopathy was noted, with the largest hilar lymph node measuring 5 cm.
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      Figure 4A hematoxylin and eosin stain of the lung parenchyma showed cryptococcal infection with intra-alveolar involvement (arrowhead) and capillary occlusions (arrow).
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      Figure 5Cryptococcal organisms in myocardial capillaries (arrow) as well as an intramyocardial cryptococcoma (arrowhead) were visible in another hematoxylin and eosin stain.
      Although we had concern for an HIV-associated opportunistic infection, a disseminated cryptococcal infection was not part of the differential diagnosis. The lymphadenopathy and pulmonary nodule seen on chest CT were subtle clues of a fungal disease, but the dramatic findings of acute right heart failure, pulmonary hypertension, and shock led us to suspect that an entity causing pulmonary vascular occlusion was to blame. Because pulmonary embolism is the most common culprit, the negative CT angiography and a low probability ventilation perfusion scan were unexpected. Had a rapid HIV test been available for inpatients at our institution, the presumptive diagnosis of HIV infection would have expanded the differential diagnosis.
      Cryptococcus neoformans is an important opportunistic infection in patients with deficits in cell-mediated immunity; for example, patients who have acquired immunodeficiency syndrome (AIDS), require immunosuppressant drugs, or are undergoing chemotherapy. Cryptococcosis is considered an AIDS-defining illness, and it characteristically causes severe meningitis when CD4 counts drop below 100 cells/μL.
      • Sloan D.
      • Dlamini S.
      • Paul N.
      • Dedicoat M.
      Treatment of acute cryptococcal meningitis in HIV infected adults, with an emphasis on resource-limited settings.
      Cryptococcal pneumonia also is common and may present as acute respiratory failure in up to 10% of patients.
      • Visnegarwala F.
      • Graviss E.A.
      • Lacke C.E.
      • et al.
      Acute respiratory failure associated with cryptococcosis in patients with AIDS: analysis of predictive factors.
      Diagnosis can be made rapidly by latex agglutination testing of serum, cerebrospinal fluid, or bronchial lavage fluid.
      • Jarvis J.N.
      • Percival A.
      • Bauman S.
      • et al.
      Evaluation of a novel point-of-care cryptococcal antigen test on serum, plasma, and urine from patients with HIV-associated cryptococcal meningitis.
      Cryptococcal disease is thought to result primarily from reactivation of latent infection, although a proportion of cases may result from a new primary infection.
      • Perfect J.R.
      • Dismukes W.E.
      • Dromer F.
      • et al.
      Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America.
      One proposed mechanism for central nervous system invasion by C. neoformans involves its expression of urease, which promotes cryptococcal sequestration within the microcapillaries. This leads to microemboli, fungal proliferation, and entry into brain parenchyma through disruption of the vessel wall.
      • Olszewski M.A.
      • Noverr M.C.
      • Chen G.-H.
      • et al.
      Urease expression by Cryptococcus neoformans promotes microvascular sequestration, thereby enhancing central nervous system invasion.
      An alternative hypothesis suggests that the fungus is transported across the blood-brain barrier by circulating phagocytic cells.
      • Charlier C.
      • Nielsen K.
      • Daou S.
      • Brigitte M.
      • Chretien F.
      • Dromer F.
      Evidence of a role for monocytes in dissemination and brain invasion by Cryptococcus neoformans.
      We postulate that in our patient's case, severe fungemia due to disseminated cryptococcal infection led to diffuse pulmonary microvascular occlusion. This ultimately resulted in profound hypoxia, rapidly progressive right heart failure, cardiovascular collapse, and ultimately, death.
      The history and time course of our patient's HIV infection is unclear. It is important to note that the Centers for Disease Control and Prevention recommends that all patients in health-care settings be routinely screened for HIV with opt-out testing; that is, patients are screened unless they explicitly refuse the test. While HIV screening has an extremely high sensitivity and specificity, it is well known that in an acute infection, a window exists before antibodies appear so that testing during this period can produce a false negative. And although opportunistic infections are sometimes seen in acute retroviral syndrome, it is more likely that our patient had a longstanding HIV/AIDS infection, and her report of a negative screening test 6 months earlier was an example of disinformation. Theoretically, the patient was screened 4 years prior if she received prenatal care for her youngest child, but the results of prior HIV testing were not available.
      Mild right ventricular hypertrophy seen on echocardiography and autopsy might suggest underlying World Health Organization Group 1 pulmonary arterial hypertension, which can be associated with HIV infection. Still, there was no evidence of plexiform lesions or medial hypertrophy on autopsy that would suggest chronic pulmonary vascular changes from pulmonary hypertension.
      To our knowledge, this is the first reported case of cardiopulmonary collapse secondary to right heart failure and pulmonary vascular occlusion from acute disseminated cryptococcal infection. Our patient's case highlights the need to maintain a high index of suspicion for HIV infection in patients with unusual clinical presentations in areas of high disease prevalence.

      Acknowledgment

      We would like to thank Dr. Lois R. Goslinoski and Forensic Photographer Matthew Brown for the pathology images.

      References

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        • Dlamini S.
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      Linked Article

      • Evidence of Pulmonary Disseminated Cryptococcosis: Diffuse Multiple Micronodules on Thoracic Computed Tomography
        The American Journal of MedicineVol. 128Issue 1
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          Sperry et al1 recently reported acute respiratory failure due to disseminated cryptococcal infection, and their pathologic analysis demonstrated Cryptococcus neoformans occluding intra-alveolar spaces and the pulmonary microvasculature. We recently described an extremely rare case2 with disseminated cryptococcosis resembling miliary tuberculosis. The patient's serum cryptococcal antigen titer was markedly elevated (1/65,536), and acute respiratory failure progressed over 4 days. After the patient's death, a diagnosis of human immunodeficiency virus infection (CD4 cell count, 12/μL) was made.
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