Case 48

Published on 18/02/2015 by admin

Filed under Allergy and Immunology

Last modified 22/04/2025

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CASE 48

RG is 45 years old and has recently returned from a trip to China. While there he visited several small local markets, as well as a number of other typical tourist sites, including the Great Wall near Beijing. Two weeks after his return he developed a fever, which seemed only to defervesce intermittently with acetaminophen. During the past 2 days he has complained to his family of feeling more short of breath than usual and has had a crushing headache. Finally, tonight his overall condition worsens and he comes to the emergency department.

This is a worrisome presentation (particularly in view of recent evidence for infection by a number of transmissible emerging viruses, including severe acute respiratory syndrome [SARS], swine flu, avian flu, West Nile virus, and so on). He should be quarantined during workup! What should you do as part of the workup? What are the treatment options?

QUESTIONS FOR GROUP DISCUSSION

1. Although this patient certainly falls within a high risk for SARS, more common disorders are still more common. How would you ensure that this is not a typical viral infection and/or community-acquired pneumonia?

2. Given that his fever of the past 2 days only abates intermittently with acetaminophen how will you treat the fever?

3. This patient is feeling more short of breath than usual. What information would you hope to gain from a chest radiograph? What tests would you perform to determine how poorly the lungs are functioning? If sufficient supplemental oxygen is not possible by mask, how would you proceed?

4. Along with the fever and difficulty breathing, RG has a crushing headache. Explain why you would request computed tomography (CT) of his head and a lumbar puncture.

5. Having ruled out common infections, what emerging infectious agents should be high on the list of possibilities, particularly given his travel history? What tests would you request?

6. Essentially all the tests that you have requested come back without dramatic results (including the CT and lumbar puncture with cultures). The white blood cell count is minimally elevated (12,000/mm³, but still only 55% neutrophils and 40% lymphocytes (normal is ∼60% neutrophils). What does this indicate regarding the type of pathogen with which RG is infected?

7. The chest radiograph shows hazy infiltrates throughout. This is consistent with the white blood cell differential (see question 6). Most importantly, your patient can only maintain an oxygen saturation greater than 92% on 60% oxygen given by re-breather mask. Therefore, it is necessary to continue oxygen therapy and to monitor this patient’s chest carefully. Explain how you would do this. Note that at this point you are still treating symptoms, not disease.

8. Serology comes back positive for West Nile virus and not for any of the other viruses of concern. What are the sequelae of West Nile viral infection? A vaccine is not available.

9. SARS is a coronavirus that has caused significant morbidity and mortality worldwide. Recent data suggest evidence for overexpression of the novel procoagulant fibroleukin in the lungs of SARS patients (a phenomenon seen also in the case of other single stranded RNA viruses, such as fulminant hepatitis C infection). What is fibroleukin? What is its normal role?

10. Discuss possible therapeutic avenues of approach regarding question 9.

RECOMMENDED APPROACH

Implication/Analysis of Family History

We are not provided with any family history; and given the urgency of the clinical presentation, the immediate goal is to treat the symptoms.

Implication/Analysis of Clinical History

RG is short of breath and has had intermittent fever for the past 2 days and a crushing headache. All of these symptoms are typical of viral infections. Despite his travel history, which must be kept in mind, we should consider first those infections that are common. Thus, you need to ensure this is not a typical infection (e.g., community-acquired pneumonia) and/or viral infection. However, he should be quarantined during workup. RG has a fever, which is only resolved intermittently; therefore, to get his temperature under control use simple measures (e.g., acetaminophen or nonsteroidal anti-inflammatory drugs) as well as sponging his body with warm water.

Common Infections

Common respiratory viral infections include influenza (types A and B), adenovirus, parainfluenza, rhinovirus, and respiratory syncytial virus (in infants). Nonculture tests are now available that provide results in minutes to hours instead of days using the conventional cell culture assays. More sophisticated assays (multiplex polymerase chain reaction [PCR]) for screening common viral infections of the nervous system have been developed in the United Kingdom, and, again, rapid results are possible. The most common cause of community (as opposed to health care facility)-acquired bacterial pneumonia is infection with Streptococcus pneumoniae, which can be determined using a rapid latex agglutination or immunochromographic assay.

Implications/Analysis of Laboratory Investigation

Routine blood work was ordered (e.g., complete blood cell count, electrolytes) as well as a chest radiograph. To determine the cause of the headaches, a CT scan was requested, as was a lumbar puncture to obtain cerebrospinal fluid (CSF) for culturing to determine if RG was infected with Neisseria meningitidis.

Blood Work, Chest Radiograph, CT

Results from the rapid diagnostic tests were all negative, indicating that the cause of RG’s illness is not a common infection. Results of the blood work indicated that the white blood cell count was minimally elevated, with the differential showing 50% neutrophils and 45% lymphocytes (normal for neutrophils is 40% to 60%; for lymphocytes it is 20% to 40%). The fact that the differential count did not indicate an increase in neutrophils suggests that this is not likely to be a bacterial infection but rather a viremia (lymphocytosis). The chest radiograph showed hazy infiltrates throughout, again consistent with viral infection. CT of the head was normal, ruling out a brain tumor. Results from the cerebrospinal fluid culture from the lumbar puncture to rule out meningitis (N. meningitidis) require several days.

Lung Function

To assess lung function, oxygen saturation with and without supplemental oxygen was requested. Sufficient oxygenation by mask delivery was evident and so intubation was not necessary. (In cases where intubation is required, appropriate precautions should be followed to protect the physician/technologist from respiratory secretions.) However, RG can only maintain an oxygen saturation greater than 92% on 60% oxygen given by re-breather mask. This is certainly in keeping with a significant respiratory compromise, and he needs to be monitored carefully with chest radiography and pulmonary function tests in an intensive care unit. An increase in lung infiltrate and respiratory distress would indicate a need for greater control of the airway (intubation).

Additional Laboratory Tests

Having ruled out common infections, it is time to test for transmissible emerging viruses including SARS, swine flu, avian flu, and West Nile virus. Serology (and PCR-DNA screening) should be sent to a specialized laboratory for SARS, as well as for other emerging viruses, including West Nile virus (see earlier).

DIAGNOSIS

Serology comes back (eventually) to indicate West Nile virus infection and not infection of any of the other viruses of concern.

THERAPY

Current therapies for West Nile virus infection have been disappointing (e.g., use of ribavirin and other novel antiviral agents).

Clinical trials to assess new therapies for patients infected with West Nile virus with serious neurologic complications are ongoing. Included in these experimental therapies are (1) IgG containing a high titer of anti–West Nile virus (Omr-IgG-am), (2) anti-sense compounds that target single-stranded RNA viruses such as West Nile, SARS, hepatitis C, dengue (AVI BioPharm NEUGENE), and (3) interferon alfa (Alferon) for West Nile meningoencephalitis.

ETIOLOGY: WEST NILE VIRUS

West Nile virus is a mosquito-borne virus that belongs to the family of flaviviruses, as do the yellow fever and dengue viruses. Individuals infected with West Nile virus may have no symptoms, whereas others may have fever and headache, become comatose, and have long-lasting neurologic damage, including muscle paralysis. Generally, most people make a complete recovery. A few will have longer-term neurologic dysfunction, probably reflecting cross-reactivity between immune response to virus and common neuronal antigens (see Cases 28 and 30).

Attempts to understand why there is such a discrepancy in response to West Nile virus infection have led to a search for susceptibility genes in murine models. A team of French scientists found a direct correlation between mortality and mutations in the gene encoding the enzyme “oligoadenylate synthetase.” The activated form of this enzyme converts the latent endonuclease, RNase L, to its active form. West Nile virus has a single-stranded RNA genome, which is a substrate for RNase L. As yet, this mutation’s association with West Nile virus has not been identified in humans.

SARS is a coronavirus that has caused significant morbidity/mortality worldwide (Fig. 48-1). A large effort is being made to develop a protective vaccine effective before and after exposure. In addition, better diagnostic and prognostic indicators are needed. Recent data suggest evidence for overexpression of the novel prothrombinase fibroleukin in the lungs of sick patients (a phenomenon seen also in the case of other single stranded RNA viruses (e.g., fulminant hepatitis C infection). Procoagulants and prothrombinases play an important role in triggering fibrin deposition and thrombosis in small vessels. Thus, measures to prevent fibroleukin overexpression are another important therapeutic avenue of approach.

FIGURE 48-1 A, Negative-stain electron micrograph of a coronavirus such as SARS. B, Portable upright chest radiograph of a previously healthy female with viral pneumonia (in this case after adenovirus infection), showing consolidation of the left lower lobe and lingual segment, along with a left-sided pleural effusion. This would not be an atypical picture in SARS (in this case after coronavirus infection).

(A, From Hart CA, Shears P: Color Atlas of Medical Microbiology, 2nd ed. St. Louis, Mosby, 2004; B, From Klinger JR, Sanchez MP, Curtin LA, et al: Multiple cases of life-threatening adenovirus pneumonia in a mental health care center. Am J Respir Crit Care Med 157:645–649, 1991.)

Note that the incidence of disease in, and severity of infection in, immunocompromised individuals is extremely enhanced relative to healthy control populations (see Transplantation, Section V). Remember that, in fact, AIDS was recognized for what it was (an acquired immunodeficiency disease) because we had already gained experience with many of the presentations (Kaposi’s sarcoma, Pneumocystic carinii (jiroveci) pneumonia) from looking after oncology patients and transplant survivors.

FURTHER READING

Ammann AJ. Leiner’s disease and C5 deficiency. J Pediatr. 1972;81:1221.

Bernard GR, et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001;344:699.

Bouffard JP, et al. Neuropathy of the brain and spinal cord in human West Nile virus infection. Clin Neuropathol. 2004;23:59.

Cook DN, Pisetsky DS, Schwartz DA. Toll-like receptors in the pathogenesis of human disease. Nat Immunol. 2004;5:975.

Das UN. Is insulin an anti-inflammatory molecule? Nutrition. 2001;17:409.

Eskola J, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med. 2001;344:403.

Gando S, et al. Activation of the extrinsic coagulation pathway in patients with severe sepsis and septic shock. Crit Care Med. 1998;26:2005.

Gioannini TL, et al. Isolation of an endotoxin-MD-2 complex that produced Toll-like receptor 4-dependent cell activation at picomolar concentrations. Proc Natl Acad Sci USA. 2004;101:4186.

Gould LH, FIkrig E. West Nile virus: A growing concern. J Clin Invest. 2004;113:1102.

Hogrefe WR, et al. Performance of immunoglobulin G (IgG) enzyme linked immunosorbent assays using a West Nile virus recombinant antigen (preM/E) for detection of West Nile virus- and other flavivirus specific antibodies. J Clin Microbiol. 2004;42:4641.

Kapoor AH, et al. Long persistence of West Nile virus (WNV) IgM antibodies in cerebral spinal fluid from patients with CNS disease. J Clin Virol. 2004;31:289.

Klee AL, et al. Long-term prognosis for clinical West Nile Virus infections. Emerg Infect Dis. 2004;10:1405.

Klugman KP, et al. A trial of a 9-valent pneumococcal conjugate vaccine in children with, and those without, HIV infection. N Engl J Med. 2003;349:1341.

Miyake K. Endotoxin recognition molecules: Toll like receptor-4-MD-2. Semin Immunol. 2004;16:11.

Nagi Y, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol. 2002;3:667.

Ohnishi T, Muroi M, Tanamoto K. MD-2 is necessary for the Toll-like receptor 4 protein to undergo glycosylation essential for its translocation to the cell surface. Clin Diagn Lab Immunol. 2003;10:405.

Thomas L. Germs. N Engl J Med. 1972;287:553.

Watson JT, Gerber SI. West Nile virus: A brief review. Pediatr Infect Dis J. 2004;23:357.

Whitney CG, et al. Decline in invasive pneumococcal disease after the introduction of protein-polysaccharide conjugate vaccine. N Engl J Med. 2003;348:1737.

Whitney CG, Pickering LK. The potential of pneumococcal conjugate vaccines for children. Pediatr Infect Dis J. 2002;21:961.

Wise RP, et al. Postlicensure safety surveillance of 7-valent pneumococcal conjugate vaccine. JAMA. 2004;292:1702.

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