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

CASE 6-1

Sixteen-Month-Old Boy

SANJEEV K. SWAMI

HISTORY OF PRESENT ILLNESS

The patient was a 16-month-old African-American male, admitted because of concerns for failure to thrive (FTT). He has also been noted by his parents to have lost some of his previously acquired developmental skills. During the week prior to admission, he has felt “warm”; his temperature was not measured. He was also having two to three loose stools per day. The stools were not bloody. He had no vomiting. He had a slight cough, but no rhinitis, rash, or ear pain. From a developmental standpoint, he was always delayed compared to his twin. He first rolled over at 10 months. He was not sitting or walking. He recently had been noted to be smiling less and interacting less. He receives early intervention services for occupational and physical therapy. The pediatrician prescribed nutritional supplements, but the family has not yet obtained them.

MEDICAL HISTORY

The boy was the first born of a twin pregnancy. His birth weight was 5 pounds and 10 ounces. He was delivered to a 20-year-old mother by Cesarean section for breech presentation. The baby has been bottle-fed and has had no previous hospitalizations. He had pneumonia at 7 months of age, which was treated in the outpatient setting. He was also treated for thrush at 9 months of age that responded promptly to oralnystatin. Otitis media was recently diagnosed and treated at the clinic.

He has no allergies and receives no medication. He has not traveled outside the United States. The only pet was an older cat. One month ago the mother was hospitalized with a cerebrovascular accident. In the process of evaluation, she was found to be HIV-antibody positive.

PHYSICAL EXAMINATION

T 37.8°C; HR 130 bpm; RR 40/min; SpO2 100% in room air

Weight 7.94 kg (<5% for an 8-month-old); Height 75.5 cm (10th percentile; 50th percentile for an 11-month-old); Head circumference 47 cm (25th percentile)

In general, the child was apathetic and irritable, but consolable in his mother’s arms. There was frontal prominence and bitemporal wasting. The tympanic membranes were normal in appearance and mobility. The oropharynx was clear; there was no thrush. Multiple small cervical, occipital, axillary, epitrochlear, and inguinal lymph nodes were palpable. The cardiac examination revealed a normal S1 and S2 with no murmurs, rubs, or gallops. The chest was clear to auscultation bilaterally. The abdomen was soft without tenderness or guarding. The liver edge was palpable 3 cm below the right costal margin while the spleen was palpable 2 cm below the left costal margin. The child was globally hypotonic but deep tendon reflexes were symmetrically increased. Plantar reflexes were down-going.

DIAGNOSTIC STUDIES

Complete blood count revealed the following: hemoglobin, 11.0 g/dL; white blood cell count, 37 900/mm3 (8% segmented neutrophils, 47% lymphocytes, 38% atypical lymphocytes); platelet count, 195 000/mm3. Serum electrolytes, blood urea nitrogen, and creatinine were normal. Additional laboratory studies included the following: lactate dehydrogenase, 1586; ALT, 98; AST, 139; alkaline phosphatase, 108; triglycerides, 212; and albumin, 3.4 mg/dL.

COURSE OF ILLNESS

HIV antibody testing was performed at the time of admission given the mother’s recent diagnosis. The child’s HIV antibodies were positive. Initial evaluation focused on determining this child’s HIV status (in utero exposure vs. true infection) since maternal HIV antibodies may be present for the first 18 months of life. Additional testing by HIV polymerase chain reaction was positive confirming this child’s diagnosis of HIV infection.

Given his HIV exposure, there was concern that his developmental regression could be secondary to HIV encephalopathy. A head CT scan, performed without contrast, revealed diffuse cerebral atrophy. Soon after hospitalization, the child began to have high fevers to 40.1°C, accompanied by tachycardia and tachypnea. His oxygenation remained adequate. After several days, he began to have persistent tachypnea with mild increased work of breathing, and occasional rales at the left lower lung field. A chest X-ray showed mild volume loss at the right upper lobe, as well as streaky atelectasis in the left lower lobe and right upper lobe. An abdominal ultrasound was obtained to look for increased retroperitoneal adenopathy, due to the possibility of disseminated Mycobacterium avium as a cause of his fevers. The abdominal ultrasound showed hepatomegaly with an increase in the echotexture of the liver, without focal masses or abscess. There was no ductal dilatation or gall-bladder wall thickening. There was also splenomegaly, without focal lesions within the spleen. Also noted were several enlarged nodes within the porta hepatis, as well as several enlarged retroperitoneal nodes in the paraortic area. The kidneys were normal.

What are the causes of fever and hepatosplenomegaly in an HIV-positive infant?

DISCUSSION CASE 6-1

DIFFERENTIAL DIAGNOSIS

There were many possible diagnoses to be considered in this case of FTT. The symptoms of diarrhea and fever were factors supporting an organic cause. However, the history of being noncompliant with obtaining the nutritional supplements and the situation of an over-stressed family with the mother having HIV and twins raised the consideration of some nonorganic factors. The possibility of mixed FTT was very high on the list.

As far as organic causes are concerned HIV is a well-known cause of FTT. Additional testing is required to differentiate between maternally transmitted antibodies and true infection in young infants. A positive PCR test confirmed true HIV infection as an explanation of the patient’s FTT. Then, the onset of high spiking fevers prompted the evaluation for an opportunistic infection.

Diagnostic considerations in an HIV-infected child with fever are diverse (Table 6-3). A child who is HIV positive and who is febrile requires an exhaustive search to identify an organism. Initial evaluation should include a search for focal infection and a general assessment of severity of illness. The absence of specific localizing signs presents a greater diagnostic dilemma.

TABLE 6-3. Differential diagnosis of fever in an HIV positive child.

Viral Infections

Hepatitis B

Hepatitis C

Herpes simplex virus

Varicella zoster virus

Cytomegalovirus

Epstein-Barr virus

Focal Bacterial Infections

Pneumonia

Sinusitis

Intra-abdominal abscess

Mycobacterial Infections

Mycobacterium tuberculosis

Mycobacterium avium complex

Fungal Infections

Pneumocystis jirovecii pneumonia

Cryptococcus neoformans

Parasites

Toxoplasma gondii

Cryptosporidium

Other

Lymphoid interstitial pneumonia

DIAGNOSIS

Toxoplasma IgM was negative, but IgG was positive, and the patient had a clinical picture consistent with disseminated toxoplasmosis. He had hepatitis, pneumonitis, and diffuse lymphadenopathy with an atypical lymphocytosis on peripheral blood smear. Ophthalmology was consulted to evaluate for retinal changes. None were present. The patient was started on therapy for toxoplasmosis, including pyrimethamine, sulfadiazine, and leucovorin rescue. The diagnosis is Toxoplasmosis gondii, an intracellular parasite.

INCIDENCE, EPIDEMIOLOGY, AND LIFECYCLE

The organism is distributed widely and rates of infection vary greatly. Sixteen to forty percent of the population is estimated to be infected in the United States and the United Kingdom, while the rates of infection in Central and South America and continental Europe are between 50% and 80%. Human infection may be asymptomatic to severe, even fatal in individuals who are immunocompromised. Felines (cats) are the only definitive host.

The routes of transmission in humans include blood transfusion, organ trans-plantation, transplacental, and ingestion of chicken eggs, meat, milk, or oocysts in contaminated water or vegetables from feline fecal matter. The lifecycle of the parasite includes a sexual phase that occurs in cats and an asexual phase that occurs in both cats and humans and other intermediate hosts (Figure 6-1). The incidence in cats, other animals, and in humans varies greatly by location and age of the population studied.

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FIGURE 6-1. Lifecycle of Toxoplasma gondii (Courtesy of the Centers for Disease Control and Prevention, Division of Parasitic Diseases and Malaria—DPDx website: http://www.dpd.cdc.gov/dpdx/Default.htm).

CLINICAL PRESENTATION

The clinical manifestations of toxoplasmosis vary depending on host factors and the timing of infection (Table 6-4). Approximately 70% to 90% of cases acquired postnatally are asymptomatic. For patients with an intact immune system the symptomatic cases most often involve lymphadenopathy with either tender or nontender nodes. These children may have a mononucleosis-like picture. In children who are immunocompromised, multiple organs may be involved. In AIDS patients, central nervous system involvement is common. Findings include headaches, hemiparesis, and visual disturbances. More severe presentations have included speech abnormalities, seizures, and the syndrome of inappropriate antidiuretic hormone secretion.

TABLE 6-4. Toxoplasmosis clinical syndromes.

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Congenital toxoplasmosis is often asymptomatic and bears no significant signs or symptoms, but 30%-40% of affected newborns will have some findings if evaluated closely. It is estimated that 1 in 3000 to 1 in 10 000 live births in the United States are afflicted by congenital toxoplasmosis. The affected newborns may have hydrocephalus, fevers, hepatosplenomegaly, prolonged hyperbilirubinemia, blindness, deafness, and other manifestations incl uding diarrhea and feeding difficulties. Ocular toxoplasmosis may be a consequence of congenital infection or postnatally acquired infection.

Infection is lifelong with acute and chronic stages. Acute illness involves a period of parasitemia following the initial infection. With chronic infection, the parasite is encysted in the host tissue. Organisms may periodically break out of the cysts resulting in local reactivation of the disease. In immunocompromised hosts, the reactivation of disease may result in dissemination and systemic spread.

Long-term sequelae of congenital toxoplasmosis include developmental delay, seizures, spasticity, visual impairment, and deafness.

DIAGNOSTIC APPROACH

Toxoplasma gondii antibodies. Serologic tests are most commonly employed and measure the host antibody represented. Toxoplasma gondii-specific IgG serum antibody, at any titer, indicates a risk of active infection in an immunocompromised individual. Testing that shows seroconversion or a fourfold or greater rise in antibody titer in serum obtained 3-6 weeks apart can confirm the diagnosis. There are several toxoplasma serologic tests available; most experts use the Palo Alto Medical Foundation Toxoplasma Serology Laboratory (http://www.pamf.org/serology/) for complicated cases.

Other studies. The infection can also be confirmed by demonstration of the organism histologically or by identification of nucleic acid (polymerase chain reaction) in a site in which the encysted organism would not be present as part of a latent infection, such as cerebrospinal fluid or bronchoalveolar fluid. When the diagnosis is made in an individual thought to be immunocompetent, HIV testing should be considered.

Lumbar puncture. The differential diagnosis of congenital toxoplasmosis is broad. Therefore, cerebrospinal fluid (CSF) testing should include cell count, protein, and glucose, and Gram stain and bacterial culture. Additionally, CSF testing should also be done for enteroviruses and herpes simplex virus by polymerase chain reaction and syphilis by CSF Venereal Diseases Research Laboratory (VDRL) testing.

Radiologic studies. A head ultrasound or CT may reveal diffuse intracranial calcifications. In contrast, intracranial calcifications in congenital cytomegalovirus infections are typically periventricular (Figure 6-2).

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FIGURE 6-2. Periventricular calcifications typically found with congenital cytomegalovirus infection.

Ophthalmology consultation. Infants with congenital toxoplasmosis may have chorioretinitis and, less commonly, microophthalmia or cataracts. Chorioretinitis occurs in most infants with neurologic disease attributed to congenital toxoplasmosis and in almost two-thirds of infants with generalized toxoplasmosis. Chorioretinitis may also be present in congenital infections caused by cytomegalovirus, herpes simplex virus, rubella, and varicella zoster virus. Microophthalmia may also be present in congenital rubella, though this disease is rare in the United States.

TREATMENT

Combination therapy is recommended for treatment of toxoplasmosis. The primary medication is pyrimethamine, a folic acid antagonist. Leucovorin is administered with pyrimethamine to help counteract its bone marrow suppressive side effects. Sulfadiazine or clindamycin is recommended as an additional treatment agent. The combination of pyrimethamine with sulfadiazine acts synergistically. Spiramycin is preferred in treating women during pregnancy. Trimethoprim-sulfamethoxazole also has efficacy in treating toxoplasmosis but is not considered to be a primary therapy. Other medications that have been used in combination with pyrimethamine include azithromycin, clarithromycin, atovaquone, and dapsone. HIV-infected patients with CD4+ T-lymphocyte counts less than 100-200/mm3 may require continued suppressive antimicrobial therapy.

SUGGESTED READINGS

1. Hill D, Dubey JP. Toxoplasma gondii: transmission, diagnosis and prevention. Clin Microbiol Infect. 2002; 8:634-640.

2. Tamma P. Toxoplasmosis. Pediatr Rev. 2007;28:470-471.

3. Weiss LM, Dubey JP. Toxoplasmosis: a history of clinical observations. Int J Parasitol. 2009;39:895-901.

4. McAuley JB. Toxoplasmosis in children. Pediatr Infect Dis J. 2008;27:161-162.

5. Montoya JG. Laboratory diagnosis of Toxoplasma gondii infection and toxoplasmosis. J Infect Dis. 2002; 185:S73-S82.