FATAL DISSEMINATED CRYPTOCOCCOSIS WITH RENAL INVOLVEMENT IN AN HIV-INFECTED PATIENT

Criptococose disseminada fatal com envolvimento renal em paciente infectado pelo HIV

SUMMARY

Introduction:

We present a fatal case of disseminated cryptococcosis in a young man whose diagnosis of HIV infection was made at the time of admission to the emergency room.

Case report:

The patient was a twenty-three-year-old man, with a history of daily fever during one month associated with diarrhea, weight loss, headache, vomiting and generalized seizures. He also had a history of diabetes mellitus, alcoholism and drug addiction. Upon physical examination the patient was pale, disoriented and had periods of agitation. White blood cells count was 3,440/mm³ (5% lymphocytes), hemoglobin was 10g/dL, platelets were 83,000/ mm³. Creatinine was 0.7 mg/dL; urea 19 mg/dL; Na, K, and liver enzymes were within normal limits. Lactic dehydrogenase was 494 IU/L. Cerebrospinal fluid (CSF) analysis revealed 10 white blood cells/mm³ (58% neutrophils, 31% lymphocytes, 11% monocytes) and 2 red blood cells/mm³. India ink test revealed six Cryptococcus yeasts/mm³. CSF glucose was 122 mg/dL and protein was 36 mg/ dL. VDRL test was negative and anti-HIV test was positive. Intravenous hydration, insulin, phenytoin, fluconazole, pyrimethamine, sulfadiazine, folinic acid, and amphotericin B were started. The patient did not improve and became obtunded and hypotensive. He was intubated and put on mechanical respiration. He received vasoactive drugs and died less than 24 hours after admission. A postmortem examination was performed and revealed disseminated cryptococcosis, with severe involvement of the kidneys.

Conclusion:

Cryptococcosis, as a rule, is a systemic disease that affects mostly immunocompromised individuals, especially patients with AIDS. When diagnosed late in its course it has a very high mortality.

KEYWORDS:
Cryptococcus sp; HIV; AIDS; Renal diseases; Acute kidney injury.

RESUMO

Introdução:

Apresentamos um caso fatal de criptococose disseminada em homem jovem cujo diagnóstico de HIV foi feito no momento da admissão na emergência.

Relato de caso:

O paciente, de 23 anos, sexo masculino, tinha história de febre diária de um mês de duração, associada à diarreia, perda de peso, cefaleia, vômitos e convulsões generalizadas. Tinha ainda história de diabetes mellitus, alcoolismo e drogadição. Ao exame físico havia palidez, desorientação e períodos de agitação. Os exames laboratoriais mostraram 3.440 leucócitos/mm³ (5% linfócitos), hemoglobina de 10 g/dL, 83,000 plaquetas/mm³, creatinina de 0,7mg/dL, ureia de 19 mg/dL, Na, K e enzimas hepáticas dentro dos limites da normalidade. A lactato desidrogenase era 494 UI/L. Análise do líquor revelou 10 leucócitos/mm³ (58% neutrófilos, 31% linfócitos, 11% monócitos) e 2 hemácias/mm³, glicose de 122 mg/dL e proteína de 36 mg/dL. A análise com tinta da Índia revelou seis blastoconídeos de Cryptococcus/mm³. O VDRL foi negativo e o anti-HIV positivo. Foi iniciado tratamento com hidratação venosa, insulina, fenitoína, fluconazol, pirimetamina, sulfadiazina, ácido folínico e anfotericina B. O paciente não apresentou melhora e evoluiu com obnubilação e hipotensão, sendo intubado e iniciada ventilação mecânica. Foram administradas drogas vasoativas, e o paciente evoluiu a óbito menos de 24h após a admissão. A autópsia revelou criptococose disseminada, com grave envolvimento renal.

Conclusão:

A criptococose é via-de-regra, doença sistêmica que afeta principalmente indivíduos imunocomprometidos, especialmente com AIDS, e quando diagnosticada tardiamente apresenta alta mortalidade.

INTRODUCTION

Cryptococcosis as a rule is a systemic mycosis, more frequently seen in patients with AIDS. It is the third most frequent opportunistic disease of the central nervous system (CNS) in this population. It can also be found in other conditions, such as patients with neoplasms, and can present a benign course³. The disease is rare in immunocompetent individuals, but there are reports of cases⁶. Its prevalence ranges from 2.9 to 13.3% in most countries, however it reaches 30% in Africa as well as in Southeast Asia countries. It represents an important cause of mortality in AIDS patients even with specific treatment.

It is estimated that there are 957,900 cases of cryptococcosis worldwide per year¹¹. Most cases are diagnosed as insidious meningoencephalitis with fever. Others (50% of the cases) present fever, headache, vomiting and altered mental status. Lack of specificity of clinical manifestations delays the diagnosis and worsens the prognosis¹¹.

We present a fatal case of disseminated cryptococcosis in a young man whose diagnosis of HIV infection was made at the time of admission to the emergency room.

CASE REPORT

A twenty-three-year-old man was admitted to the emergency room of an infectious disease hospital in Northeast Brazil with a one-month history of daily fever associated to diarrhea with mucus and weight loss of fifteen kilograms in six months. One week prior to admission, the patient's clinical picture worsened with headache, vomiting, disorientation and generalized tonic-clonic seizures. The patient also had a history of diabetes mellitus, tobacco smoking, alcoholism and drug addiction. He had no prior history of hospitalization. Upon physical examination the patient was pale, disoriented, and had periods of agitation. He had rhonchi on the pulmonary auscultation. Abdomen was tender on palpation of the upper right quadrant, liver and spleen were not palpable and no edema was seen in the lower extremities. Nuchal rigidity and meningeal irritation signs were present, however motor deficit was not identified.

Laboratory tests upon admission showed hemoglobin 10 g/dL, 3,440 leukocytes/mm³, (4% bands, 45% neutrophils, 5% lymphocytes), 83,000 platelets/mm³, urea was 19 mg/dL, creatinine 0.7 mg/dL, ionic calcium 1.23 mEq/L, sodium 130 mEq/L, potassium 4.2 mEq/L, and liver enzymes (ALT and AST) were within normal limits; lactic dehydrogenase was 494 IU/L. Cerebrospinal fluid (CSF) analysis revealed 10 white blood cells/mm³ (58% neutrophils, 31% lymphocytes, 11% monocytes) and 2 red blood cells/mm³. CSF glucose was 122 mg/dL and protein 36 mg/ dL. India ink test revealed six Cryptococcus yeasts/mm³. VDRL test was negative and anti-HIV test positive. CD4 count was 40/mm³. Blood glucose was 344 mg/dL. Intravenous hydration, insulin, phenytoin, fluconazole, pyrimethamine, sulfadiazine, folinic acid, and amphotericin B were started. The patient did not improve and became obtunded and hypotensive. He was then intubated and put on mechanical ventilation. Arterial blood gases after intubation: pH 7.52, PaCO₂ 28.9 mmHg, HCO₃ 26.6 mmEq/L, PaO₂ 77.9 mmHg, SaO₂ 96.6% and FiO₂ 70%. Vasoactive drugs were added and the patient died less than 24 hours after admission. A post-mortem examination was performed and revealed disseminated cryptococcosis. The histopathology of the kidneys revealed severe renal involvement with Cryptococcus sp. in the glomerulus and interstitium (Fig. 1).

Fig. 1
Main renal findings. (a) Renal biopsy showing numerous encapsulated yeast forms (Cryptococcus sp.) in glomerulus, interstitium and in (b) renal tubule (black arrow). PAS 400x.

DISCUSSION

We presented a fatal case of cryptococcosis, in which the patient only sought medical attention a month after symptoms' onset. In a prospective study in Brazil, from 1998 to 2003, 96 cases of cryptococcosis were diagnosed microbiologically and 78 (81.25%) had AIDS⁴. Cryptococcosis was diagnosed by direct microscopy in 98.3% of cases, however the culture revealed Cryptococcus in 100%. The latex agglutination test is considered a very sensitive and specific technique in the detection of this fungus in CSF. It can be used to monitor treatment as well as in diagnosing relapses after an seemingly successful therapy. In a Brazilian study, despite appropriate treatment, 70 patients died (72.9%); 60 (62.5%) of these deaths occurred in AIDS patients, demonstrating that this systemic mycosis is accompanied by a very high mortality⁴. In another cohort of patients with cryptococcosis, in Thailand, favorable clinical response was observed in 55.2% of cases, and the six month survival rate was 67.2%². Even in immunocompetent individuals, mortality due to cryptococcal infection can be as high as 51%⁸. Our patient had diabetes mellitus, which seems to be a risk factor for developing disseminated cryptococcosis due to defects in the host defense mechanisms associated with hyperglycemia⁹. A recent study highlighted possible mechanisms to explain the pathophysiology of HIV-associated cryptococcosis. It was demonstrated that high levels of fungal uptake by macrophages in vitro, but not the intracellular proliferation rate, were associated with cerebrospinal fluid fungal burden and long-term patient survival. Highuptake strains were hypocapsular and exhibited enhanced laccase activity. Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF and resistance to clearance following the patient antifungal treatment¹².

There is little data published on kidney involvement in cryptococcosis. This case report illustrates the presence of Cryptococcus in the glomerulus, interstitium and renal tubules. As the disease had a rapid and fatal course,

there was no specific clinical or laboratory manifestation of kidney involvement, only the unquestionable presence of Cryptococcus in kidney histopathology. Kidney involvement in cryptococcosis is rarely described. The fungus has already been isolated in the urine of HIV-infected patients, evidencing its tropism to the kidneys⁷. In a recent study of 49 patients with cryptococcosis and without HIV, acute kidney injury was seen in 47% of cases⁸. BOLLÉE et al.¹ reported the case of an HIV-infected patient with acute kidney injury due to disseminated cryptococcosis, which was successfully treated with plasma exchange therapy. This patient has also developed nephrotic range proteinuria, which evidenced glomerular involvement in cryptococcosis¹. RAMDIAL et al.¹⁰ described the cases of two HIV-infected children with cryptococcosis complicated by renal involvement. Renal biopsy showed cryptococcal-associated immune reconstitution inflammatory syndrome in one of these patients based on the clinicopathological profile and the presence of segmental glomerular and an interstitial lymphoplasmacytic and granulomatous reaction to Cryptococcus neoformans, with predominance of capsuledeficient fungal forms. The other patient presented typical HIV-associated nephropathy with focal intra-tubular and interstitial C. neoformans yeasts in renal biopsy¹⁰. The exact pathophysiology of kidney involvement in cryptococcosis remains unclear.

Recommendations for specific treatment of cryptococcal meningoencephalitis can be found in the Brazilian cryptococcosis guidelines⁵. According to the guidelines, treatment should initiate with 0.7 to 1.0 mg/kg/day of amphotericin B (maximum 50 mg), associated with 5-flucytosine in a dose of 100 mg/kg/day, given for two weeks as induction treatment. After this period, oral fluconazole 400 mg/day is indicated, for 10 weeks, as a maintenance therapy⁵. It is possible that the use of other antifungal agents, such as voriconazole or posaconazole, could change this fatal outcome, particularly in immunosuppressed patients, as in vitro studies have demonstrated an excellent effect of these drugs on this fungus¹¹.

In the present case, the disease severity and the fast evolution to death in less than 24 hours after hospital admission did not allow appropriate treatment, started with fluconazole.

In conclusion, cryptococcosis is a systemic mycosis that affects immunocompromised patients, with a high frequency among HIVinfected individuals, mainly those who develop AIDS. It presents as a severe disease with high mortality, especially when the diagnosis is delayed.

REFERENCES

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  Rothe C, Sloan DJ, Goodson P, Chikafa J, Mukaka M, Denis B, et al. A prospective longitudinal study of the clinical outcomes from cryptococcal meningitis following treatment induction with 800 mg oral fluconazole in Blantyre, Malawi. PLOS ONE. 2013;8:e67311.
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Publication Dates

• Publication in this collection
  Jul-Aug 2015

History

• Received
  15 Oct 2014
• Accepted
  10 Nov 2014