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Dr. I. David Todres (Pediatric Intensive Care): An eighteen-year-old man was admitted to the hospital in shock after a five-day illness.
The patient had been in good health until five days before admission, when cough and myalgias developed. The next day, he was seen at a college health service and given a cough suppressant. The day after, he was seen by a physician at the health service. His lungs were clear, and a diagnosis of bronchitis was made. Azithromycin and albuterol by metered-dose inhaler were prescribed, and the patient started taking the antibiotic the following day. His temperature rose to 39.4°C, and post-tussive vomiting, diarrhea, and generalized body aches developed. He returned from college to his family's home and spent most of the day in bed. On the day before admission, he noticed mottling of the skin, and he was seen that evening at a neighborhood health clinic. His blood pressure was 125/98 mm Hg, the heart rate 157 beats per minute, respirations 28 per minute, temperature 36.3°C, and oxygen saturation 99 percent while he was breathing room air. His skin was pale, the heart sounds were normal except for tachycardia, and the head, lungs, and abdomen were normal. Intravenous normal saline and metoclopramide were administered, and he was sent home with instructions to return if he felt worse.
On the morning of admission, he reported headache, stiff neck, pleuritic chest pain, and increasing myalgias in his back and extremities. His limbs were cold. His family brought him to the emergency room of this hospital.
His medical history included obesity, hypercholesterolemia, acne, and a left varicocele. Between two and three years before admission, he had lost 50 kg in weight and the hypercholesterolemia had resolved. The weight was 100 kg, and the height 187 cm four months before admission. He had received all childhood immunizations, including hepatitis B vaccine; he was offered the meningococcal vaccine before starting college but had declined it. He had not received influenza vaccine. He had no allergies. He resided in a college dormitory, and he smoked cigarettes and drank alcohol. He had had several unprotected sexual encounters. His only sick contact was a friend who had been given a diagnosis of mononucleosis one month earlier. He reported no recent travel or unusual exposures. He had taken a dietary supplement for weight loss that did not contain ephedra in the past but had been told by his physician to discontinue it four months before admission. His current medications were albuterol and azithromycin. His mother and sibling were healthy but obese; an uncle had died of melanoma; his grandfather had leukemia.
On examination he appeared acutely ill and uncomfortable but was alert and responsive, with occasional tachypnea and vomiting. His temperature was 33.9°C orally and 36.1°C rectally, blood pressure 140/61 mm Hg, pulse 120 beats per minute, and respirations 16 to 32 per minute. The neck was supple, and the lungs were clear. There was tenderness to palpation over the spine and the muscles of the back and extremities. The skin was mottled, without petechiae; the extremities were cool and clammy, with acral cyanosis. The rest of the examination was normal.
Laboratory values are shown in Table 1, Table 2, and Table 3. An electrocardiogram showed a rate of 118 beats per minute, a PR interval of 125 msec, QRS duration of 88 msec, QT of 292 msec, corrected QT of 409 msec, and ST-segment changes consistent with early repolarization or pericarditis. A chest radiograph was normal (Figure 1A), and a bedside echocardiogram showed no pericardial fluid. Specimens of blood, urine, and sputum were taken for bacterial and viral cultures and testing for viral antigens. A rapid influenza screening of a nasal swab was negative. Intravenous vancomycin, ceftriaxone, and normal saline fluid boluses totaling 3.5 liters, morphine, and ketorolac were administered. He was admitted to the pediatric intensive care unit.
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On the morning of the second hospital day, the blood pressure was 116/17 mm Hg, the pulse 177 beats per minute, and the temperature 39.6°C. Acetaminophen was given. A chest radiograph revealed decreased lung volumes and the development of perihilar indistinctness, which may have reflected interstitial edema or developing viral pneumonia, and slight enlargement of the cardiac silhouette (Figure 1B). Toxicology screening of blood was negative except for the presence of doxylamine (0.02 mg per liter). Twenty-nine hours after presentation the axillary temperature was 40.4°C (104.8°F) and the blood pressure 82/55 mm Hg despite increasing doses of dopamine, epinephrine, and norepinephrine. A transthoracic echocardiogram revealed an estimated ejection fraction of 47 percent, diffusely hypokinetic ventricles, and an underfilled left ventricle. There was a moderate apical and posterior pericardial effusion. Dobutamine treatment was begun again, and fluid administration was increased. The lung sounds were coarse, with secretions ranging from scant and thin to moderately creamy. The results of laboratory tests are shown in Table 1, Table 2, and Table 3.
Thirty-one hours after presentation, bradycardia developed, followed rapidly by asystole, and cardiopulmonary resuscitation was initiated. Epinephrine and atropine boluses, bicarbonate, calcium, isoproterenol, insulin, and intravenous fluids were administered. Defibrillation with electroshock and external and internal pacing were attempted, without evidence of capture. The patient was pronounced dead 32 hours after arrival in the emergency room. The microbiology laboratory reported the detection of influenza A antigen in a nasal swab obtained on the previous day. An autopsy was performed.
Differential Diagnosis
Dr. Todres: May we review the chest radiograph and the echocardiograms?
Dr. Jo-Anne O. Shepard: The chest radiograph obtained on admission reveals well-inflated, clear lungs and no evidence of a pleural effusion. The heart is normal in size (Figure 1A). A portable chest radiograph obtained on the second hospital day, after intubation and the placement of a nasogastric tube, revealed lower lung volumes and the development of perihilar indistinctness that may have reflected interstitial edema or developing viral pneumonia (Figure 1B). The cardiac silhouette is slightly larger, most likely owing to a small pericardial effusion.
Dr. John G. Morgan: The most striking finding on the echocardiogram is an increase in the thickness of both the left and right ventricular walls (Figure 2). The interventricular septum is 20 mm thick, and the posterior left ventricular wall is 26 mm at end diastole (upper limit of normal, 11 mm). The right ventricular free wall is 11 mm (upper limit of normal, 5 mm). The left ventricular cavity is small at 34 mm, suggesting underfilling, despite fluid resuscitation. The left ventricular function is mildly reduced globally. There is a small-to-moderate circumferential pericardial effusion with more fluid located posteriorly and at the apex. There is no evidence of diastolic inversion of either ventricle, and only transient inversion of the left atrium, which make cardiac tamponade unlikely. The respiratory variation across the mitral and tricuspid valves was normal, also suggesting that the pericardial effusion was not hemodynamically significant. There was no mitral or aortic regurgitation to explain the patient's hemodynamic instability.
Dr. Julie L. Gerberding: This patient acquired influenza A in late 2003, during a widespread national outbreak. The 2003–2004 influenza season started unusually early and rapidly progressed across the entire United States (Figure 3). Early reports of deaths among children aroused concern that the influenza A subtype — influenza A/Fujian/411/2002-like virus (H3N2) — that was responsible for nearly all cases might be especially virulent among otherwise healthy children. This teenager required treatment in the pediatric intensive care unit just five days after an influenza-like illness developed. A rapid influenza-antigen detection test was negative at the time of hospitalization, but influenza A antigen was subsequently detected with a more sensitive laboratory test. Although the patient had no known predisposition to severe complications of influenza, he had clinical evidence of shock, rhabdomyolysis, acute renal failure, and myopericarditis, and he died on the second hospital day.
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Influenza Outbreaks and Pandemics
Influenza A and B viruses can cause widespread outbreaks of human disease with devastating consequences.4,5,6 Influenza A viruses are classified on the basis of the characteristics of two surface glycoproteins, hemagglutinin (H1 to H15) and neuraminidase (N1 to N9). All subtypes have been detected in viruses recovered from aquatic birds, which are the natural reservoir for influenzaviruses. So far, only H1, H2, and H3 and N1 and N2 are associated with large-scale influenza outbreaks among humans. Hemagglutinin attaches to sialic acid receptors on respiratory epithelial cells and is the major antigenic determinant to which vaccine-induced neutralizing antibody is directed. Neuraminidase enzymatically cleaves glycosidic linkages to sialic acid so that progeny virions can leave infected cells. It is less important in immunity, but is the target of a new class of antiviral drugs, the neuraminidase inhibitors oseltamivir and zanamivir.
Influenzaviruses contain single-strand negative-sense segmented RNA that encodes at least 10 proteins. A hallmark of influenzaviruses is their capacity to evolve in a short time frame. New strains emerge each year as a consequence of antigenic drift, through point mutations in the surface glycopeptides; hence the requirement for a new vaccine each year.4,5,6 Antigenic shift refers to the emergence of influenza viruses bearing a novel hemagglutinin or hemagglutinin and neuraminidase combination. Antigenic shift is caused by reassortment of the segmented genome, which occurs when two influenza A viruses with different hemagglutinin subtypes infect a common host, usually a pig, and genomic segments are exchanged (Figure 4). When reassortment involves human and animal influenzaviruses and produces a subtype that has not recently circulated in the population, a pandemic may develop.
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Influenza viruses replicate in ciliated columnar respiratory epithelium, especially in large airways. Viremia is uncommon. Influenza is efficiently transmitted from person to person through exposure to droplets generated by coughing and sneezing, through indirect contact with contaminated fomites, and in some instances, through inhalation of infectious aerosols. The incubation period ranges from one to four days (average, two).4,5 People are usually infectious from the day before the onset of symptoms to about three to five days after they appear. Up to 50 percent of infected persons have no symptoms but may be infectious. Children and immunosuppressed persons may remain infectious much longer than normal adults.
There were three major influenza pandemics in the 20th century (Figure 5).5,6 The 1918–1919 influenza A (H1N1) ("Spanish flu") epidemic caused 20 million to 50 million deaths around the world and more than 500,000 deaths in the United States. Influenza A (H1) strains continued to cause seasonal outbreaks until 1958, when influenza A (H2N2) ("Asian flu") emerged. Since the population was not immune to the new H2 antigen, another pandemic developed, causing about 70,000 deaths in the United States. In 1968, influenza A (H3) ("Hong Kong flu") caused a third pandemic, which resulted in approximately 50,000 deaths in the United States. In 1977, H1 reappeared as the dominant hemagglutinin subtype, but a true pandemic did not occur, since most people more than 20 years old had prior exposure to this subtype antigen and had residual immunity. Since 1997, influenza A H3 and H1 subtypes as well as influenza B strains have been in circulation. Trivalent vaccines have therefore been necessary to ensure protection.4,5
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Influenza Surveillance
Influenza has a striking seasonal occurrence in temperate climates, but it occurs year-round in the tropics. The onset of flu season is highly variable and difficult to predict. In the Northern Hemisphere, it usually starts in November or December and subsides before May. In the Southern Hemisphere, the season usually begins in May and subsides by October. From the global perspective, strains of influenza are always circulating somewhere in the world, in a never-ending pattern of evolution that portends the eventual appearance of a pandemic and challenges the capability and scheduling of vaccine production.
At the CDC, we conduct surveillance to determine where, when, and what influenzaviruses are circulating.3,4 These data are used to determine whether influenza activity is increasing or decreasing, but because only a minority of people with respiratory illness are tested for influenza, they are not used to ascertain how many people have become ill with influenza or the spectrum of complications they may have. Reports come from selected laboratories worldwide, a network of health care providers in the United States, the vital-statistics offices of selected U.S. cities, and state health departments, which report influenza activity as "no activity," "sporadic," "local," "regional," or "widespread" (Figure 3).
Complications of Influenza
The risk of serious influenza complications is increased among persons with underlying chronic medical conditions or immunodeficiency, pregnant women, infants and very young children, and the elderly.4,8,9,10 Morbidity and mortality are usually higher in years in which H3N2 subtypes predominate than in years in which H1N1 or B viruses predominate.
The most frequent complication of influenza is exacerbation of an underlying medical condition, such as chronic cardiovascular or pulmonary disease. The patient discussed here had no known medical conditions to account for his rapidly fatal clinical course, although he had been overweight and he smoked tobacco. It is possible that he had an undiagnosed cardiomyopathy or immunodeficiency, but there is no evidence.
Given the widespread outbreak of influenza in the community, the positive laboratory test for influenzavirus in this patient could have been coincidental to an unrelated diagnosis. His residence in a college dormitory is a risk factor for communicable diseases associated with crowding, including Neisseria meningitidis meningitis and septicemia. The antimicrobial drugs he took before hospitalization could have inhibited the growth of bacteria in laboratory cultures and made it difficult to establish the diagnosis of bacterial infection. The absence of other cases of meningitis in the community and the prominent cardiac features of his illness argue against this diagnosis, but empirical treatment was appropriate. Likewise, toxic shock caused by streptococci or staphylococci or a toxic ingestion could certainly have accounted for many of his initial symptoms and signs, but there is no supporting evidence for these diagnoses.11
Influenza in healthy older children and young adults is usually a tracheobronchitis; pneumonia and other serious complications are rare, and mortality is low. However, in the 1918–1919 pandemic, morbidity and mortality rates among healthy men and women 20 to 40 years of age were higher than in any other age stratum.12,13 Most deaths were attributable to respiratory failure, with clinical and pathological findings suggestive of either primary viral pneumonia or secondary bacterial pneumonia. Among the first 93 children under 18 years of age with fatal influenza reported to the CDC during this influenza season, 25 had pneumonia, 15 bacterial.2 In this patient, the absence of pulmonary infiltrates, the preservation of gas exchange, and the absence of laboratory evidence suggestive of bacterial infection argue against a diagnosis of bacterial pneumonia as a cause of death.
Myocarditis, pericarditis, and rhabdomyolysis are known complications of both influenza A and influenza B infection.5 Some descriptions suggest that myocarditis may have been frequent during the 1918–1919 influenza pandemic, especially among young, otherwise healthy patients, but it is difficult to extrapolate the incidence of this condition from the available data. Since 1919, isolated cases and small clusters of influenza-induced myocarditis, alone or in conjunction with pericarditis or rhabdomyolysis, have been reported.14,15,16,17,18,19,20,21,22 In a case series from Japan, patients with myocarditis during the 1998–1999 season had electrocardiographic changes, echocardiographic abnormalities, and creatine kinase elevations four to seven days after the onset of influenza symptoms, a time frame similar to that of this patient's illness.20 Some studies suggest that the incidence of myocardial inflammation, as diagnosed by minor electrocardiographic abnormalities, associated with influenza may be as high as 9 to 10 percent.17 However, in a recent prospective cohort study of 152 patients in England that used measurement of cardiac troponins I and T to detect myocardial injury, none of the 12 percent of patients with elevated creatine kinase levels had evidence of cardiac involvement, suggesting that rhabdomyolysis is more common than myocarditis.22
Influenzavirus has been detected in cardiac muscle and in pericardial fluid and tissue, but direct invasion is often not apparent, even when sensitive immunohistochemical stains are used for detection.23 Most systemic effects of influenzavirus infection are caused by cytokine release, rather than direct infection of the tissue. The spectrum of influenza-induced skeletal-muscle and cardiac disease, the cellular mechanism of tissue injury, and the effect of involvement of these tissues on mortality among otherwise healthy people require further elucidation.
I believe the explanation for this patient's rapidly fatal course is multifactoral, with myopericarditis and refractory low-output cardiogenic shock, complicated by renal insufficiency secondary to rhabdomyolysis and myoglobinuria.
Dr. Nancy Lee Harris (Pathology): Dr. Luginbuhl, you were the infectious-disease consultant for this patient; can you give us your clinical impressions?
Dr. Lynn M. Luginbuhl (Pediatric Infectious Disease): When we first saw this young man, we thought that he most likely had influenza, despite the negative bedside test, given his upper respiratory tract symptoms, the rhabdomyolysis, and the known early onset of the influenza season. We were very concerned about secondary bacterial sepsis, particularly meningococcal disease, mycoplasmal pneumonia, and streptococcal or staphylococcal toxin–mediated disease, so we used broad antibiotic coverage. We considered the possibility of myocarditis because of the abnormal echocardiogram, but we thought that the decreased ejection fraction was due to myocardial dysfunction from septic shock. We gave activated protein C for possible bacterial septic shock and because acute respiratory distress syndrome seemed to be developing. At the time of death the clinical picture remained one of irreversible shock, and we were still concerned that he had a secondary bacterial infection. We then learned that he was influenza A–positive, and we knew that no bacteria had grown at 24 hours. Thus, we began to consider the possibility that his death might be due to influenza A alone.
Clinical Diagnosis
Influenza A infection with shock, caused by either bacterial superinfection or possibly influenza, complicated by rhabdomyolysis, renal failure, and disseminated intravascular coagulation.
Dr. Julie L. Gerberding's Diagnosis
Influenza A infection with shock due to multiple factors, including possible myopericarditis and severe rhabdomyolysis with myoglobinuria and renal failure.
Pathological Discussion
Dr. Harris: Dr. Richard L. Kradin will present the autopsy findings.
Dr. Richard L. Kradin: At autopsy, the tracheobronchial tree was diffusely erythematous and the respiratory epithelium was denuded. Microscopically, the trachea and large bronchi were congested and edematous and contained submucosal hemorrhage and a mononuclear-cell inflammatory infiltrate. The epithelium was denuded, and there was patchy reparative squamous reepithelialization (Figure 6A). The lungs weighed 2800 g together and were plum colored, congested, and edematous, but with minimal consolidation. The alveoli were filled with macrophages and desquamated epithelium. There was early hyaline membrane formation and proliferation of alveolar type II pneumocytes, findings consistent with diffuse alveolar damage (Figure 6B). No viral inclusions were identified, and there was no evidence of bacterial infection. The influenza A virus isolated from the sputum was subtyped as H3N2. Immunohistochemical staining performed at the CDC identified influenza A nucleocapsid protein within pulmonary epithelial cells (Figure 6C). All postmortem fluids, including sputum, blood, urine, and cerebrospinal fluid, were negative for bacterial growth.
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Skeletal muscle showed severe rhabdomyolysis with numerous degenerating and necrotic muscle fibers, marked edema, and focal infiltration of neutrophils (Figure 6E). Immunostaining of cardiac and skeletal muscle at the CDC did not reveal evidence of influenzavirus. The renal glomeruli were normal, but the proximal tubules contained pigmented casts (Figure 6F), which were shown by immunostaining to be myoglobin (inset, Figure 6F). There was severe ischemic hepatic injury with centrilobular necrosis. The adrenal glands were normal.
Influenza produces no consistent cytopathic changes. Uncomplicated infection causes tracheobronchitis characterized by necrosis, ulceration, and denudation of the respiratory epithelium, followed by reparative squamous reepithelialization. The pathological changes of influenza pneumonia26 include bronchiolocentric exudation of histiocytes, obliterative bronchiolitis with organizing pneumonia, and diffuse alveolar damage with necrosis and hemorrhage. Myocarditis is rare, but myocardial inflammatory-cell infiltrates were observed at autopsy in approximately one third of 33 patients dying from influenza.27 Although myalgias are common, severe rhabdomyolysis is unusual; it occurs more often in young patients and can be complicated by myoglobinuria and renal failure, as in this case.28,29,30,31,32 Skeletal-muscle biopsies generally do not reveal direct viral infection.33
The mechanisms of viral pathogenesis are most likely complex. In addition to direct viral replication in epithelial cells, proinflammatory cytokine release34 and abnormalities in the interferon system35 may contribute to the morbidity and mortality. In this case, death is attributable to multisystem disease complicating influenza A H3N2 infection, including tracheobronchitis, pneumonia, possible early myopericarditis, severe rhabdomyolysis with myoglobinuria and acute renal failure, disseminated intravascular coagulation, and hepatic centrilobular necrosis. The striking cardiac hypertrophy , which may have been associated with the patient's history of obesity,36 may have placed him at increased risk for complications.
A Physician: Would early initiation of antiviral therapy have altered the course?
Dr. Gerberding: Antiviral drugs have been documented to shorten the course of the illness by only a day or two. One study of oseltamivir found that treatment may reduce some complications,37 but no studies have shown that treatment reduces fatal outcomes.
Dr. Harris: I wonder whether severe rhabdomyolysis could be the dominant cause of the shock-like symptoms in this patient's clinical presentation. Influenza A is the most common infectious cause of rhabdomyolysis.28,29,30,31,32 Severe rhabdomyolysis can lead to shock due to massive fluid redistribution into necrotic muscle, respiratory acidosis, disseminated intravascular coagulation, and myoglobinuria with renal failure, all of which were seen in this case.31 He had unremitting hypovolemic shock, despite a net fluid gain of over 20 liters in 32 hours. Although his weight was 100 kg four months earlier, the autopsy service recorded his weight as 144 kg, suggesting that a remarkable amount of extravascular fluid had accumulated. In one reported case of a child with fatal rhabdomyolysis associated with influenza B infection, muscle biopsy showed a clinically unsuspected carnitine palmitoyl transferase II deficiency.38 It is possible that an unrecognized metabolic disorder may predispose patients to rhabdomyolysis in influenza A infection.
Dr. Gerberding: This tragic case reminds us that influenzavirus is a serious pathogen and that we need to do more to prevent this very preventable illness through vaccination programs.
Anatomical Diagnoses
Influenza A infection with rhabdomyolysis, severe; myoglobinuria; viral tracheobronchitis and pneumonia; virus-associated cardiac changes ("borderline myocarditis") and catecholamine-induced myonecrosis; pericardial effusion.
Disseminated intravascular coagulation.
Hepatic centrilobular necrosis.
Cardiac hypertrophy of unknown cause.
Source Information
From the Centers for Disease Control and Prevention, Atlanta (J.L.G.); and the Cardiac Echo Lab and Department of Medicine (J.G.M.), Department of Radiology (J.O.S.), and Department of Pathology (R.L.K.), Massachusetts General Hospital and Harvard Medical School.
References
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Related Letters:
Case 9-2004: An 18-Year-Old Man with Respiratory Symptoms and Shock
Kopterides P., Todres I. D.
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N Engl J Med 2004;
351:105-106, Jul 1, 2004.
Correspondence
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