Disseminated cryptococcosis in a patient with newly diagnosed HTLV-1 infection

Abstract

Infection by human T-lymphotropic virus 1 (HTLV-1) is often seen as the cause of chronic infection or lymphoproliferative disorders, but many clinicians do not recognise its association with severe immunosuppression. We report the case of a woman in her 70s from the Caribbean who sought care at the emergency department for weakness, fatigue and weight loss. Further work-up showed atypical lymphocytosis with floral lymphocytes and smudge cells in the peripheral blood smear and hypercalcaemia. Chest CT demonstrated a moderate right pleural effusion. Results of HIV testing were negative, and screening and confirmatory tests for HTLV-1 were positive. Empiric antibiotic therapy was administered, and the patient was discharged home. Five days later, she was readmitted with shortness of breath and severe abdominal pain. A disseminated infection with Cryptococcus neoformans was diagnosed. Despite aggressive intravenous antifungal therapy, the patient died on day 7 of hospitalisation.

Background

Cryptococcal infections are ubiquitous and are associated with increased morbidity and mortality rates, especially in immunocompromised patients.¹ Conditions known to increase the risk of cryptococcal disease include HIV infection, AIDS, solid organ transplant, malignant processes, cirrhosis, systemic lupus erythematosus and sarcoidosis.²

Only a few reports have been published of pulmonary cryptococcosis in patients with human T-lymphotropic virus 1 (HTLV-1)-associated adult T-cell leukaemia/lymphoma (ATLL).^{3 4} Similarly, descriptions of disseminated cryptococcal disease in patients with HTLV-1 ATLL are scarce.⁵ As a result, many clinicians in non-endemic areas remain unaware of the risk of cryptococcosis in HTLV-1-infected patients.

We report a case of disseminated cryptococcosis in a patient with an HTLV-1-associated T-cell lymphoproliferative disorder.

Case presentation

A black woman in her 70s who was born in Haiti was brought by her family to the emergency department for concerns of weakness, fatigue and weight loss for 1 month. She had immigrated to the USA more than 10 years earlier. She had a history of coronary artery disease and type 2 diabetes. On admission, the physical examination revealed an afebrile patient with axillary lymphadenopathy and cachexia. Laboratory test results showed a normal white blood cell count (9.5×10⁹/L) with lymphocytosis (absolute count, 6.6×10⁹/L), thrombocytopenia (platelet count, 136×10⁹/L), borderline lactic acidosis (lactate, 2.3 mmol/L) and hypercalcaemia (corrected calcium, 13.1 mg/dL). Chest CT showed a consolidation in the right lung apex with moderate right pleural effusion (figure 1). Peripheral blood smear showed atypical lymphocytosis (28%) with floral lymphocytes and smudge cells. Testing for serum HIV type 1 and 2 antibodies wa negative, and plasma HIV-1 RNA reverse transcription was undetectable.

Figure 1.

Patient imaging. (A) Chest radiograph at admission shows a new small right pleural effusion with adjacent right lower lobe consolidation. (B) Chest CT without contrast at admission confirms a moderate right pleural effusion. (C) CT angiography at readmission shows moderate bilateral pleural effusions, unchanged in the right lower lobe and increased in the left lower lobe, and no evidence of pulmonary embolus. (D) Follow-up CT 4 days after ultrasound-guided paracentesis shows increased lower right pleural effusion and decreased small left pleural effusion.

Investigations

Blood cultures obtained on admission were negative. Tuberculosis testing with QuantiFERON-TB Gold (QIAGEN) was indeterminate secondary to a low response to mitogen. Induced sputum bacterial culture grew normal respiratory flora. Three induced sputum acid-fast bacilli smears were negative.

Thoracentesis was performed. The blood cell count was significant for 529 white blood cells/μL with 47% lymphocytes. Pleural fluid was exudative according to Light’s criteria. Cytological findings were significant for mesothelial cells and atypical lymphocytes. Pleural fluid bacterial, fungal and mycobacterial cultures were negative.

An axillary lymph node biopsy was performed. Pathological analysis ruled out metastatic carcinoma, but the specimen was not sufficient to evaluate for a lymphoproliferative disorder.

Serum screening and confirmatory tests for HTLV-1/2 antibodies were positive; a discrimination assay was positive for HTLV-1. Flow cytometry immunophenotyping and T-cell receptor rearrangement studies from blood were concerning for adult T-cell lymphoproliferative disorder.

Differential diagnosis

The patient was a woman in her 70s, with a remote history of immigrating to the USA from Haiti, who had constitutional symptoms, lymphadenopathy and chest CT findings concerning for pneumonia. The initial concern for this patient was pulmonary tuberculosis with or without HIV infection. After tests for these conditions were negative, the next possible diagnosis was lymphoma complicated by bacterial pneumonia. Because the patient was of Haitian origin, HTLV was of high concern as a risk factor for possible lymphoma. Her antibody test results were positive for HTLV-1, and flow cytometry findings strongly suggested T-cell lymphoma. After this diagnosis was made, her lung findings were attributed to community-acquired bacterial pneumonia, and no further respiratory sampling was obtained.

Treatment

Empiric antimicrobial treatment for pneumonia with ceftriaxone and azithromycin was started. The patient was treated with calcitonin, bisphosphonate and intravenous fluids for her hypercalcaemia, and she improved clinically. She was discharged to a skilled nursing facility with plans for outpatient work-up and management of her HTLV-1-associated lymphoma.

Five days later, she was readmitted to the hospital because of severe abdominal pain and shortness of breath. CT of the abdomen and pelvis showed copious abdominal and pelvic ascites, large bilateral pleural effusions, and diffuse abdominal and pelvic lymphadenopathy. Ultrasound-guided paracentesis yielded 1.4 L of clear yellow fluid, and the patient was started on intravenous piperacillin–tazobactam. On the third day of admission, she became hypotensive and required transfer to the intensive care unit. At 74 hours, bacterial blood cultures were positive for Cryptococcus neoformans. Intravenous amphotericin B and oral 5-fluorocytosine were initiated. Her serum cryptococcal antigen titre was 1:640 (CrAg LFA; IMMY, Norman, Oklahoma, USA). Fungal cultures of pleural fluid, bronchoalveolar lavage and ascitic fluid were positive for cryptococcus. A lumbar puncture was ordered but could not be obtained because of the patient’s marked clinical deterioration.

Outcome and follow-up

On the fourth day of hospitalisation, the patient went into cardiac arrest but was resuscitated and intubated. She required multiple vasopressors. Despite aggressive therapy with intravenous amphotericin B and oral 5-fluorocytosine, she died on day 7 of hospitalisation.

Discussion

C. neoformans is an encapsulated yeast that causes life-threatening infections in immunocompromised patients. Classically, C. neoformans causes pulmonary and central nervous system infections in persons who are HIV-positive.⁶ It also causes infections in other patients with impairment of T-cell immunity such as solid organ transplant recipients.⁷ It is now recognised that almost half of new cryptococcus cases occur in persons who are HIV-negative.⁸ In immunocompromised hosts, cryptococcal infection carries a high mortality rate of up to 20% and is uniformly fatal without treatment.⁶

Contrary to the ubiquitous distribution of C. neoformans, HTLV-1 has been described in clusters in highly endemic areas in southwestern Japan, the Caribbean, West Africa and South America.⁹ The estimated seroprevalence of HTLV-1 in endemic areas is 1%—2%, and it increases gradually with age, reaching a 20%—40% prevalence in persons aged 50 years and older.⁹ In the 1990s, HTLV-1 seropositivity in rural Haiti ranged from 2.2%—5.3%.¹⁰

HTLV-1 infection typically has been linked with ATLL, tropical spastic paraparesis, parasitic infections, tuberculosis and viral hepatitis.¹¹ Interestingly, ATLL is more aggressive among the Afro-Caribbean population than among Japanese patients, and hypercalcaemia has been described with acute presentation and poor survival.¹²

Some studies and case reports have suggested a link between HTLV-1 and cryptococcal infection. A study in French Guiana found that 12.1% of patients admitted to the hospital with cryptococcal infection were positive for HTLV-1.¹³ A few case reports have documented pulmonary cryptococcosis in patients with HTLV-1 infection. One report described an 82-year-old woman who, similar to our patient, had diagnoses of HTLV-1 infection and disseminated cryptococcosis in a brief interval.⁵ This patient also died during hospitalisation. Another earlier case report and series reported four cases of cryptococcal pneumonia in patients with HTLV-1 and ATLL, as well as several cases of pneumocystis pneumonia.³ This highlights the severe impairment of the immune system that HTLV-1 can cause.

HTLV-1 has been proposed to cause a chronic deleterious effect on cellular immunity. HTLV-1 infects human T cells and leads to alterations in cellular behaviour.¹⁴ HTLV-1 infection stimulates a T_H1 immune response and is associated with a weaker T_H2 response.¹⁵ HTLV-1 leads to a truncated interaction between dysfunctional infected T cells and macrophages.¹⁶ These changes in cellular immunity are seen clinically by an increased prevalence of parasitic infections and active tuberculosis in HTLV-1-infected patients, particularly in areas of high endemicity.^{15 17 18}

This case report illustrates the severe immunosuppression that can result from HTLV-1 infection. It is also a reminder of the rapid lethality of opportunistic infections like cryptococcus. Given this, clinicians need to maintain a high level of suspicion for cryptococcus when approaching diagnosis and treatment in HTLV-1-infected patients.

Learning points.

• A high level of immunosuppression should be considered in patients with human T-lymphotropic virus 1 (HTLV-1) infection.

• Severe opportunistic infections such as cryptococcosis can occur in patients with HTLV-1 infection.

• A judicious clinical approach to rule out opportunistic infections should be used to diagnose and treat life-threatening infections early in patients with HTLV-1.

• In patients for whom there is a high suspicion of cryptococcal infection, a low threshold for starting appropriate anticryptococcal therapy is necessary.