Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 11-3

Fourteen-Year-Old Boy

MATTHEW TEST

SAMIR S. SHAH

HISTORY OF PRESENT ILLNESS

A 14-year-old boy was brought to the emergency department for evaluation of prolonged fever and new seizures. Eight days prior to admission, he developed fever to 38.3°C. Two days prior to admission, he complained of headache and continued fevers. On the day before admission he was standing in the kitchen talking to his aunt when he fell to the floor and had tonic flexion of his arms associated with eye deviation. This event lasted approximately 2 minutes. He was evaluated at a nearby hospital. His temperature was 38.6°C, but the physical examination was normal. He was discharged after a normal noncontrast head CT was obtained. On the day of admission, he was taken to his pediatrician’s office for evaluation of continued fever. Shortly after arriving at the office, he had a similar event with arm flexion and eye deviation. It did not resolve spontaneously, and the boy was rushed to the hospital by ambulance. He received several doses of lorazepam without termination of apparent seizure activity. He required endotracheal intubation due to respiratory failure. Seizures were ultimately controlled with the combination of fosphenytoin and valproic acid.

The boy’s aunt, the primary caretaker, related that during the past month he had several episodes of fecal soiling. Additionally, he had a documented 8-pound weight loss. The most striking information, however, was the marked deterioration in handwriting that occurred during the same time period. Furthermore, in the past month he had frequently neglected his household chores, a change from his baseline demeanor that was attributed to “teenage hormones.” Aside from the two recent events, she did not recall any seizure activity. There were no rashes, emesis, or diarrhea. He performed well in school except during the past month, during which he failed several tests. This change in school performance was attributed to poor vision, and an ophthalmology appointment had been scheduled for later in the month.

MEDICAL HISTORY

The boy had not previously required hospitalization. He was adopted by his aunt in infancy while his biological mother struggled with drug addiction. She had died recently, but the aunt did not know the cause of death. The patient lived in an urban area and had no pets.

PHYSICAL EXAMINATION

T 38.4°C; HR 93 bpm; RR 18/min; BP 193/98 mmHg

Prior to endotracheal intubation his Glasgow Coma Score was 8. After stabilization, corneal reflexes were present. The gag reflex was intact. The tongue was midline. However, there was no spontaneous eye opening. Although he did not respond to voice or blink with direct visual confrontation, he localized painful stimuli. His tone was increased in the lower extremities. Babinski sign was negative bilaterally. His neck was supple. Heart and lung sounds were normal. The liver was palpable 3 cm below the right costal margin, with a total span of 11 cm.

DIAGNOSTIC STUDIES

Serum electrolytes were normal. Serum glucose was 119 mg/dL. Serum ammonia level was normal. Complete blood count revealed the following: 11 500 WBCs/mm3 (73% segmented neutrophils and 22% lymphocytes); hemoglobin, 11.7 g/dL; and 785 000 platelets/mm3. Prothrombin and partial thromboplastin times, fibrinogen, and fibrin split products were normal. Noncontrast head CT, obtained before lumbar puncture, revealed normal-sized ventricles and no masses. CSF analysis revealed 1 WBC/mm3 and 630 RBCs/mm3. The protein and glucose concentrations were 53 mg/dL and 52 mg/dL, respectively.

COURSE OF ILLNESS

Gram stain of the cerebrospinal fluid revealed some yeast forms. Magnetic resonance imaging of the head was significantly abnormal (Figure 11-3). What is the most likely diagnosis?

Image

FIGURE 11-3. Magnetic resonance image of the head.

DISCUSSION CASE 11-3

DIFFERENTIAL DIAGNOSIS

The boy’s initial complaint of prolonged fever precipitated medical evaluation. However, the history of behavioral changes, worsening school performance, and seizures was even more alarming. The development of status epilepticus at the pediatrician’s office ultimately prompted a more thorough investigation of his symptoms. It was not clear at this point whether the patient has an encephalitis or encephalopathy. Although bacterial meningitis causes fever and seizures, the absence of CSF pleocytosis and the chronicity of symptoms made typical bacterial meningitis unlikely. Bacterial causes of encephalitis include Borrelia burgdorferiBartonella henselae (cat-scratch disease), Rickettsia rickettsia, and Ana-plasma phagocytophilum. Residence in an urban area made B. burgdorferi, the causative agent of Lyme disease, unlikely. Patients critically ill with R. rickettsia (Rocky Mountain spotted fever) infection typically have hyponatremia, hypoalbuminemia, anemia, and mild thrombocytopenia, findings not present in this case. Most, but not all, patients with cat-scratch disease have a clear history of contact with a cat or, more likely, a kitten. Again, the chronic symptoms, if related to the fever and seizures, are not typically seen with any of the above illnesses.

Viral causes of encephalitis include enteroviruses, arthropod-borne viruses (e.g., West Nile virus, St. Louis encephalitis virus, Eastern equine encephalitis virus), herpes simplex virus, Epstein-Barr virus, adenovirus, influenza, and human immunodeficiency virus (HIV). In adolescents, herpes simplex virus usually causes focal seizures and radiologic changes localized to the temporal lobe. There were no clear risk factors for HIV based on the initial history. The other viruses do not usually cause the progressive neurologic symptoms seen in this child.

Although this child’s history did not have worrying indications for immunodeficiency, several infectious conditions can present with subacute symptoms in immunocompromised patients. Patients with humoral deficiencies may develop a chronic enteroviral meningoencephalitis. Those with cell-mediated immune deficiencies are at risk for subacute herpes simplex virus encephalitis, varicella-zoster virus encephalitis, and progressive multifocal leukoencephalopathy. Patients with AIDS can develop central nervous system infection with Toxoplasma gondii and Cryptococcus neoformans, an encapsulated yeast. These patients can also develop HIV-related encephalopathy.

The finding of yeast forms upon CSF Gram stain is helpful. Occasionally, degenerating WBCs are mistaken for yeast forms but additional investigation of this finding is clearly warranted. Meningitis due to Candida species typically occurs in patients with indwelling venous catheters, sustained neutropenia, and hyperglycemia due to diabetes, glucocorticoids, or hyperalimentation; none of which was present in this patient. In this case, the finding of yeast forms upon Gram stain of the CSF strongly suggested the diagnosis of cryptococcal meningitis.

Noninfectious causes include acute drug or medication ingestions as well as lead intoxication. Central nervous system vasculitis caused by either systemic lupus erythematous or polyarteritis nodosa should be strongly considered in the differential diagnosis.

DIAGNOSIS

Head MRI revealed dilatation of the Virchow-Robin spaces in the white matter, especially in the basal ganglion and thalamus, a finding seen with cryptococcal meningitis (Figure 11-3). The MRI also revealed dilatation of the lateral and third ventricles and sulci seen with HIV encephalitis. There was also abnormally increased signal in the periventricular white matter bilaterally, a finding consistent with HIV-related encephalitis. Cryptococcus neoformans, the yeast identified on Gram stain of the CSF, was isolated from cultures of the blood and CSF. Serum cryptococcal antigen was positive at 1:1024. The CSF cryptococcal antigen was also elevated at 1:512. HIV antibody testing was positive. Additional data, gathering by the family revealed the patient’s birth mother had died from HIV-related complications. The family did not previously know the birth mother’s HIV status, and as a consequence the patient had never undergone HIV testing. The diagnosis was perinatally acquired HIV infection manifesting as cryptococcal meningitis and HIV encephalitis. The patient died on the third day of hospitalization.

EPIDEMIOLOGY AND INCIDENCE

Cryptococcus neoformans, a ubiquitous encapsulated yeast, causes diseases ranging from asymptomatic pulmonary colonization to life-threatening meningitis. Cryptococcal infection may occur in healthy persons, but most infected patients have some immunocompromising factor such as immune suppression related to organ transplantation or HIV infection. Other predisposing conditions of childhood include primary immunodeficiency (e.g., hyper-immunoglobulin M syndrome) and certain malignancies (e.g., acute lymphoblastic leukemia). Primary infection occurs through the inhalation of aerosolized soil particles containing C. neoformans. Central nervous system involvement results from hematogenous dissemination.

Cryptococcal infection has been documented in up to 2.8% of organ transplant recipients, most often in those receiving renal transplants (80% of infections), but occasionally after liver (10% of infections) or heart (5% of infections) transplantation. Cryptococcal infection occurs in up to 15% of HIV-infected adults, typically when CD4+ T-lymphocyte count declines to less than 50 cells/mm3. In contrast, this infection occurs in fewer than 2% of HIV-infected children, probably reflecting their lower exposure to sources of C. neoformans in the environment. Cryptococcus neoformans antibodies are detectable in only 4% of school-age children but in two-thirds of adults. Sources of Cryptococcus include pigeon droppings and soil.

Neonatal cryptococcal infection has been rarely reported. Transplacental vertical transmission has been implicated as the cause in these cases.

CLINICAL PRESENTATION

Cryptococcal infection may present with acute or chronic symptoms. In children, findings in acute primary pulmonary infection have not been adequately characterized, because most cases are disseminated at the time of diagnosis. In adults, presentation of primary pulmonary cryptococcal infection ranges from asymptomatic nodules in the lungs to severe pneumonia. One half of adults develop cough and chest pain. Less often, they present with fever, hemoptysis, and weight loss. In immunocompromised patients, the risk of dissemination is high enough that patients presenting with findings of pulmonary cryptococcal infection are presumed to have extrapulmonary disease. In severely immunocompromised patients, pulmonary involvement may be minimal if dissemination occurs shortly after exposure. On examination, signs of respiratory involvement include tachypnea, accessory muscle use, and decreased breath sounds.

Symptoms of cryptococcal meningitis include low-grade fever, malaise, and headache. Nausea, vomiting, altered mentation, and photophobia are less common. Stiff neck, focal neurologic deficits, and seizures are rare. Physical examination findings of cryptococcal meningitis are not sufficiently characteristic to distinguish it from other causes of meningitis. Findings may include nuchal rigidity and photophobia; however, these are typically not observed, particularly in immunocompromised patients.

Although the lungs and CNS are the most common sites of infection, dissemination occasionally affects other organs, including the skin, liver, spleen, adrenal glands, kidneys, bone, and joints. Cutaneous manifestations of cryptococcal infection include erythematous or verrucous papules, nodules, or pustules. Occasionally acneiform lesions or granulomas are noted. The lesions are usually located on the face and neck but may occur anywhere on the body.

DIAGNOSTIC APPROACH

Sputum culture. The sputum fungal culture can be used to diagnose cryptococcal pneumonia. Although isolation from the sputum may be helpful, it is important to note that asymptomatic colonization of the respiratory tract does occur.

Blood culture. Cryptococcus neoformans may grow in 3 days but occasionally takes up to 3 weeks.

Cryptococcal polysaccharide antigen by latex agglutination. The cryptococcal antigen test can be performed on serum and CSF specimens. This test should be performed on the serum of any HIV-infected patient who develops pneumonia and has a CD4+ count less than 200/mm3. This test should also be performed in any patient with suspected cryptococcal pneumonia. A positive serum test indicates disseminated infection. The serum antigen test is positive in 85%-90% of patients with central nervous system involvement. False negative results can occur at both very low and very high antigen concentrations. At high antigen concentration, this is known as the prozone phenomenon, and it is thought to occur as a result of interference with appropriate antigen-antibody interaction necessary for a positive test result. This phenomenon can be overcome through serial dilution of the sample.

Lumbar puncture. CSF should be examined in all immunocompromised patients with suspected cryptococcal infection, even if signs and symptoms of meningitis are absent. CSF specimens should be sent for cell count, protein, glucose, cultures for bacterial, fungal, and viral pathogens, and cryptococcal polysaccharide antigen by latex agglutination. Lumbar puncture classically reveals an increased opening pressure. There are typically less than 100 WBCs/mm3 (mostly lymphocytes and monocytes), although some patients may not demonstrate a pleocytosis. The glucose is less than 50 mg/dL in 65% of patients, and there may be a mild elevation of the CSF protein. Positive CSF culture on Sabouraund agar remains the gold standard in the diagnosis of cryptococcal meningitis. Cultures are positive in 90% of patients with central nervous system disease. CSF cryptococcal antigen titers of 1:4 or higher also confirm the diagnosis. CSF antigen testing is positive in nearly all patients with cryptococcal meningitis. Budding yeasts are visualized by India ink stain in 50% of cases, but this test is not required if cryptococcal antigen testing is performed. Real-time polymerase chain reaction assays have been developed for the identification of C. neoformans. These assays have sensitivities similar to that of cryptococcal antigen testing.

Serum electrolytes. Hyponatremia complicates cryptococcal meningitis, and its development portends a poor prognosis.

Radiologic studies. Chest radiography may reveal parenchymal infiltrates with air bronchograms, diffuse nodular infiltrates and, occasionally, small bilateral pleural effusions. However, in many cases, chest radiography is unremarkable. CT or MRI of the head may demonstrate granulomatous lesions (cryptococcomas), white matter changes, and increased intracranial pressure.

HIV testing. All patients diagnosed with cryptococcal meningitis or disseminated cryptococcal infection should undergo evaluation for immune deficiency, particularly HIV infection.

Cryptococcal antigen dipstick. A point-of-care dipstick for the detection of cryptococcal antigen has been developed for use on whole blood, serum, or urine. Identification of antigen with the dipstick was strongly correlated with ELISA-identification of cryptococcal antigen. Although not yet widely used, this test has the potential to improve cryptococcal diagnosis, particularly in resource-limited settings, due to its low cost, ease of use, and noninvasiveness.

TREATMENT

Clinical management varies depending on the extent of disease and immune status of the host. An asymptomatic normal host with isolated pulmonary nodules does not require treatment if the serum cryptococcal antigen test is negative. Patients with mild-to-moderate pulmonary disease require treatment with fluconazole for 6-12 months. Immunocompromised and immuno-competent patients with either severe pulmonary disease or cryptococcemia are treated in the same manner as patients with central nervous system disease. After primary therapy is complete, there is no consensus on how long HIV-negative immunocompromised patients require fluconazole prophylaxis. Most experts suggest providing prophylaxis for 1 year after the completion of acute antifungal treatment and then reassess its ongoing need based on the level of immunosuppression at that time. Treatment may be discontinued when the immune function returns to normal (e.g., after completion of chemotherapy).

HIV-positive patients and organ transplant patients with meningitis are treated with intravenous amphotericin plus flucytosine for at least 2 weeks; if the CSF culture is negative on repeat lumbar puncture, they may receive fluconazole for an additional 8 weeks. Non-HIV infected, nontransplant hosts should receive intravenous amphotericin plus flucytosine for 4 weeks, followed by 8 weeks of fluconazole. The strength of the recommendations for non-HIV infected, non-transplant hosts is impacted by the limited number of studies in this population. Additionally, the available studies are further limited by heterogeneous patient populations, ranging from normal hosts to those with malignancy and liver disease, and the administration of lower doses of antifungal therapy than are currently recommended.

Regardless of immune status, extended therapy with amphotericin and flucytosine may be considered for any patient with neurologic complications, prolonged coma, clinical deterioration or lack of improvement, and/or persistence of CSF infection.

HIV-infected patients with pulmonary or disseminated cryptococcal infection require treatment with fluconazole that continues indefinitely. The rate of relapse in HIV-infected patients is 100% without maintenance of antifungal therapy. The relapse rate decreases from 18% to 25% with itraconazole prophylaxis and 2% to 3% with fluconazole prophylaxis. Due to advances in antiretroviral therapy, some authors propose discontinuation of secondary prophylaxis for cryptococcal meningitis in HIV-infected patients if the CD4 cell count has increased above 100/mm3 and HIV viral load has been low or undetectable for longer than 3 months. If maintenance therapy is discontinued, monitoring for relapse of infection and regular monitoring of cryptococcal antigen and CD4+ cell count are recommended.

Untreated cryptococcal infection in HIV-infected patients is uniformly fatal. Survival rates are high with early diagnosis and treatment, but relapse rates are high without lifelong antifungal prophylaxis. Factors associated with poor prognosis include low weight, hyponatremia, high CSF antigen titre, low CSF WBC count, and alteration in mental status at the time of diagnosis.

SUGGESTED READINGS

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5. Jackson A, van der Horst C. New insights in the prevention, diagnosis, and treatment of Cryptococcal meningitis. Curr HIV/AIDS Rep. 2012;9:267-277.

6. Mirza SA, Phelan M, Rimland D, et al. The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992-2000. Clin Infect Dis. 2003;36:789-794.

7. Pappas PG, Perfect JR, Cloud GA, et al. Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy. Clin Infect Dis. 2001;33:690- 699.

8. Powderly WG. Current approach to the acute management of cryptococcal infections. J Infect Dis. 2000; 41:18-22.

9. Perfect JR, Dismukes WE, Dromer F, et al. Practice guidelines for the management of cryptococcal disease. Clin Infect Dis. 2010;50:291-322.

10. Saag MS, Powderly WG, Cloud GA, et al. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. N Engl J Med. 1992;326:83-89.

11. Severo CB, Xavier MO, Gazzoni AF, Severo LC. Cryptococcosis in children. Ped Resp Rev. 2009;10:166-171.