SUDDEN NATURAL DEATH | Infectious Diseases

Introduction

A wide range of deaths from natural causes is encountered in the field of forensic medicine. Despite the advances in the diagnosis and treatment of infectious diseases, a substantial number of sudden and unexpected deaths are caused by infections. In most medicolegal systems these deaths are subject to a forensic investigation.

The World Health Organization defines sudden death as that occurring within 24 h of the onset of symptoms. Some authors variably define sudden death as that occurring within 1, 6, and 12 h of the onset of symptoms.

Forensic pathologists should be aware of the importance of infectious causes of sudden death in the present era of bioterrorism and emergent and reemergent diseases. Genetic engineering has led to the development of highly infectious and virulent strains of microorganisms (e.g., anthrax). Emerging infectious diseases are infections whose incidence has increased in recent years and/or threatens to increase in the near future. Reemergence refers to the reappearance of a known infection after a period of disappearance or decline.

Death from infectious agents may occur as a direct consequence of the infection or from complications such as immunosuppression caused by the infection and adverse reactions to therapeutic drugs. Sudden death due to infectious disease may be classified by organ system involvement (e.g., cardiac – myocarditis; nervous system – meningitis and encephalitis) or according to the etiological agent (e.g., viral, chlamydial, bacterial, fungal, protozoal, or helminthic). The common infectious causes of sudden death by organ system are listed in Table 1 .

Table 1.

Common infectious causes of sudden death

Cardiovascular system
Myocarditis	Coxsackie A and B
	Chlamydia pneumoniae
	Corynebacterium diphtheriae, Neisseria meningitidis, Borrelia burgdorferi, Mycobacterium tuberculosis
	Chagas disease (Trypanosoma cruzi)
	Hydatid disease (Echinococcus granulosus)
Infective endocarditis	Staphylococcus, Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, Kingella, Candida
Respiratory system
Acute epiglottitis	Haemophilus influenzae
Pneumonia	Respiratory syncytial virus, parainfluenza virus, adenovirus, influenza A and B, severe acute respiratory syndrome (SARS), Streptococcus pneumoniae, staphylococci, H. influenzae, Pseudomonas aeruginosa, coliform bacteria, Legionella pneumophila, Pneumocystis carinii
Central nervous system
Meningitis	H. influenzae, S. pneumoniae, N. meningitides, Cryptococcus
Encephalitis	Herpes simplex virus-1
	Toxoplasmosis, malaria
Gastrointestinal system
Peptic ulcer	Helicobacter pylori
Enterocolitis	Vibrio cholerae, Clostridium perfringens, Salmonella, Shigella, enteroinvasive Escherichia coli, Entamoeba histolytica

The morphological findings at autopsy will depend on the type of organism, the site involved, and the host's response to the organism. Microbiological demonstration of an organism does not equate to disease, as a host may be colonized by bacteria or the patient may have an asymptomatic viral infection. The exquisite sensitivity of molecular tests, e.g., polymerase chain reaction, may exacerbate this problem if the results are not correlated with the pathological findings at autopsy.

Infectious Causes of Sudden Death

Categories of human pathogens include prions; viruses; chlamydiae, rickettsiae, and mycoplasmas; bacteria; fungi; protozoans; and helminths. Infection by prions, rickettsiae, and mycoplasmas is not normally associated with sudden and unexpected death.

Viral Causes of Sudden Death

Viruses are ubiquitous and cause a spectrum of disease in humans. These may range from asymptomatic infection, severe debilitating illness, to sudden death. Viral infections causing sudden death usually involve the cardiac, respiratory, or the central nervous system. Morphologic findings in viral infections may include intranuclear and/or intracytoplasmic inclusions, multinucleate giant cells, and tissue necrosis (cytopathic effect). In many cases the diagnosis can only be made on special investigations, e.g., culture, electron microscopy, serology, or molecular testing.

Viral hemorrhagic fevers such as Marburg, Lassa, and Ebola virus may cause sudden death in children. If there is any suspicion of a viral hemorrhagic fever, special care must be taken to avoid unwarranted exposure to health workers. The local public health officials must be informed and consideration given to limited autopsy examination in consultation with a virologist (e.g., postmortem blood sampling and liver biopsy).

Viral infections of the cardiovascular system

Cardiac involvement usually takes the form of myocarditis. Although many viruses may cause myocarditis (Table 2 ), coxsackie A and B are responsible for most cases. Fulminant coxsackievirus infection may also cause leptomeningitis, florid interstitial pneumonitis, pancreatitis, and focal hepatic necrosis. Coxsackie B viruses should also be considered as a cause of sudden infant death.

Table 2.

Viral causes of myocarditis

Adenovirus
Cytomegalovirus
Epstein–Barr virus
Herpes simplex virus 1 and 2
Human immunodeficiency virus 1 (HIV-1)
Influenza A and influenza B
Parvovirus
Picornavirus (e.g., enterovirus and coxsackievirus A and B)
Respiratory syncytial virus
Rotavirus
Varicella-zoster virus

At autopsy, the myocardium is usually mottled and flabby. Histology reveals focal infiltrates of inflammatory cells (neutrophils and/or lymphocytes, plasma cells, and macrophages). At least two foci of individual myofiber necrosis associated with 5–10 inflammatory cells are required for the histological diagnosis of myocarditis. Focal aggregates of lymphocytes not associated with necrosis may be seen in elderly patients and are not diagnostic of myocarditis. Myocardial involvement may be patchy. For adequate histological sampling, it is recommended that at least six sections be taken from various areas of the myocardium, including the left ventricle and nodal tissue.

Indirect damage to the myocardium may occur as an allergic response to a viral infection and eosinophilia, e.g., in eosinophilic myocarditis. This is a rare cause of sudden death in apparently healthy children due to the cardiac toxicity of eosinophils.

Studies have shown that persons undergoing severe mental or physical stress may have reduced immunity to viral infections. In the investigation of sudden death in athletes, the diagnosis of viral myocarditis must be considered.

Enteroviral infection may also play an important role in coronary plaque instability and may precipitate coronary thrombosis, leading to ventricular tachyarrhythmias and sudden death.

Viral infections of the respiratory system

Sudden death due to viral involvement of the respiratory system may be due to fulminant viral pneumonitis or bacterial pneumonia complicating an initial viral pneumonitis. Viruses implicated include respiratory syncytial virus, human herpesvirus-6, and parainfluenza virus in children, and adenovirus and influenza A and B in adults.

Microscopically, the findings of a viral pneumonitis are usually nonspecific and include edema and widening of the interstitial septa with a mononuclear cell infiltrate. In some cases, diagnostic viral inclusions may be demonstrated.

Emergent diseases such as severe acute respiratory syndrome (SARS) have a high mortality and may cause death within hours. SARS refers to an acute respiratory illness caused by infection with a novel coronavirus currently known as the SARS virus.

Postmortem histopathological evaluations of lung tissue show diffuse alveolar damage consistent with the pathologic manifestations of acute respiratory distress syndrome. There is usually mild interstitial inflammation with scattered alveolar pneumocytes showing cytomegaly, and enlarged nuclei with prominent nucleoli.

When faced with the finding of diffuse alveolar damage at autopsy, the pathologist should consider other infective causes such as influenza, para influenza, respiratory syncytial, and adenoviruses, Chlamydia, Mycoplasma, Pneumococcus, Legionella, and Pneumocystis.

Viral infections of the central nervous system

Sudden death may occur due to direct infection of the nervous system or a complication of a viral infection such as toxoplasmosis in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Herpes simplex virus-1 encephalitis is usually due to reactivation of latent infection. Commonly affected sites include the temporal lobe(s) (medial before lateral), the inferior frontal lobe(s), and the Sylvian cortex(es). At autopsy there is widespread and asymmetrical necrosis. In fulminant cases there is prominent hemorrhage and swelling with raised intracranial pressure and brain herniation. Histological findings include perivascular cuffing by mononuclear cells (Figure 1 ) and, in a small number of cases, intranuclear inclusions may be seen in astrocytes and neurons.

Figure 1.

Viral meningoencephalitis. Insert: perivascular cuffing by lymphocytes.

In adult HIV infections, sudden death from infective causes may be due to opportunistic infections (e.g., toxoplasmosis) or rupture of mycotic aneurysms.

In viral central nervous system infections the brain may appear macroscopically normal, especially in very young, elderly, debilitated, and immunocompromised individuals. Specimens should be taken for microbiology and histology. Serum and cerebrospinal fluid (CSF) should be sent for antibody studies. Tissue for histological examination should be taken from normal, obviously abnormal, and transition areas. Routine sections should be taken from the cerebral cortex (all four lobes), thalamus, basal ganglia, hippocampus, brainstem, and cerebellum. As poliomyelitis has been described as a cause of sudden death in infants, autopsy protocols in sudden death should include histological examination of spinal cord and dorsal root ganglia.

Chlamydial Causes of Sudden Death

Chlamydia pneumoniae may be associated with myocarditis and sudden unexpected death.

Bacterial Causes of Sudden Death

Bacterial infections are responsible for sudden unexpected death in adults and children. In the pediatric population bacterial infections of the respiratory, gastrointestinal, and central nervous system account for the majority of cases of sudden death.

Bacterial infections of the cardiovascular system

Bacterial causes of myocarditis include Corynebacterium diphtheriae, Neisseria meningitidis, and Borrelia burgdorferi. In B. burgdorferi, cardiac involvement occurs in 1–8% of cases and death may occur as a result of conduction disturbances. In diphtheritic myocarditis myocardial damage is caused by the release of toxins. Bartonella-induced silent myocarditis has been described as a cause of sudden unexpected cardiac death in athletes.

Granulomatous myocarditis may also lead to sudden death (Table 3 ). The mechanism of death includes arrhythmias, cardiac rupture, coronary occlusion, obstruction to pulmonary blood flow leading to fatal hemorrhage, and impaired myocardial contractility.

Table 3.

Differential diagnosis of granulomatous myocarditis

Disease	Histological features
Giant-cell/Fiedler's myocarditis	Noncaseating granulomas with adjacent muscle necrosis ± giant cells
Tuberculosis	Caseous necrosis with Langhan's giant cells
Sarcoidosis	Noncaseating granulomas with myocardial fibrosis
	Schaumann and asteroid bodies
	Calcium oxalate crystals within giant cells
Syphilis	Gummata with necrosis
	Sparse epithelioid cells
Brucellosis	Myocardial abscesses and endocarditis
Tularemia	Tuberculoid granulomas
Fungi	Granulomas with or without necrosis
	Hyphae and yeasts

Cardiac tuberculosis is usually an autopsy diagnosis. Histological examination of the myocardium shows a nodular, miliary, or diffuse infiltrative pattern. The coronary arteries may show narrowing or complete occlusion due to an intimal or diffuse tuberculous arteritis. It is uncommon to demonstrate acid-fast bacilli within the lesions. Molecular tests such as the ligase chain reaction (LCR) and polymerase chain reaction (PCR) may be used to demonstrate the organism.

Sudden death in infective endocarditis occurs as a result of perforation of a free-wall myocardial abscess or rupture of a valve leaflet. Staphylococcus aureus is responsible for 10–20% of cases and is the major cause in intravenous drug abusers. Other bacterial causes include Haemophilus, Actinobacillus, Cardiobacterium, Eikenella, and Kingella (HACEK group). Negative bacterial cultures may be found in 10% of cases as a result of prior antibiotic therapy. The most common sites of infection are the aortic and mitral valves, except in intravenous drug abusers, where the right-sided valves are primarily affected.

Tertiary syphilis causing aortitis may cause sudden death from rupture of aortic aneurysms with aortic dissection. The mechanism of death is either blood loss with hypovolemic shock or a fatal cardiac tamponade from intrapericardial rupture.

Bacterial infections of the respiratory system

Sudden death from acute epiglottitis occurs from respiratory obstruction caused by swelling of the epiglottic folds, uvula, and vocal cords. The most common cause of acute epiglottitis in developing countries is Haemophilus influenzae type B. In countries with established immunization programs, the incidence of H. influenzae epiglottitis has decreased and other bacteria, such as streptococcus, staphylococcus, and pneumococcus, have been implicated as possible causes. Postmortem blood cultures are positive in 50–75% of cases.

Lobar pneumonia (Figure 2 ) and confluent bronchopneumonia are the most frequent cause of sudden death from acute pulmonary disease. Some 90–95% of lobar pneumonia is due to Streptococcus pneumoniae type 3. Bronchopneumonia is caused by staphylococci, streptococci, H. influenzae, Pseudomonas aeruginosa, and coliform bacteria.

Figure 2.

Lobar pneumonia. Left lung, showing consolidation of the lower lobe. Insert: alveolar spaces filled with acute inflammatory exudate.

Pulmonary tuberculosis may result in hemoptysis, which can cause hypovolemic shock and sudden death. Histologically, caseating granulomas are found. Acid-fast bacilli are demonstrated using the Ziehl–Neelsen stain (Figure 3 ).

Figure 3.

Tuberculosis. Acid-fast bacilli demonstrated using a Ziehl–Neelsen stain.

Corynebacterium diphtheriae produces a gray pseudomembrane from the pharynx to the larynx, and this may lead to respiratory obstruction and sudden death.

Legionnaire's disease is associated with outbreaks of sudden death. The disease is caused by Legionella pneumophila, a facultative intracellular organism. It causes severe pneumonia in the elderly, in smokers, and in immunocompromised patients. The organisms may be transmitted via droplet spread from contaminated air-conditioning units and water coolers. The organism may be demonstrated by a modified silver stain (Dieterle stain) or by immunofluorescence and culture.

Bacterial infections of the central nervous system

Pyogenic meningitis may cause sudden death. The causative organism varies according to the age of the patient (Table 4 ).

Table 4.

Bacterial causes of acute meningitis according to age group

Age group	Organisms
Neonates	Escherichia coli
	Streptococci
	Listeria monocytogenes
Children	Haemophilus influenzae
	Neisseria meningitidis
Adults	Neisseria meningitidis
	Streptococcus pneumoniae
Elderly	Streptococcus pneumoniae
	Listeria monocytogenes

The location of the exudates depends on the organism. In H. influenzae it is basally located. In pneumococcal meningitis it occurs over the convexities of the brain in the parasagittal region (Figure 4 ). Microscopic examination reveals neutrophils filling the subarachnoid space with extension of the inflammation into the leptomeningeal veins in fulminant cases.

Figure 4.

Bacterial meningitis. Exudate demonstrated over convexities and base of the brain.

Blood spread is the most common means of entry; however other routes of infection include local extension of infection, e.g., paranasal sinusitis, osteomyelitis, direct implantation, and via the peripheral nervous system.

Diffuse bacterial meningitis may follow rupture of a brain abscess, which may lead to sudden death.

The organisms may be demonstrated by microbiological culture of the CSF and examination of Gram stains of the CSF and brain tissue.

Bacterial urogenital tract infections

Fulminant acute bacterial pyelonephritis may lead to septicemia, causing sudden death. At autopsy, the kidneys show tubular necrosis with interstitial suppurative inflammation. Renal papillary necrosis may also be present.

Bacterial infections of the gastrointestinal tract

Severe bacterial enterocolitis may lead to sudden death, especially in the young. The pathogenesis of the diarrhea depends on the cause. Vibrio cholerae and Clostridium perfringens cause diarrhea by ingestion of a preformed toxin that is present in contaminated foods. Enteroinvasive organisms such as Salmonella, Shigella, and enteroinvasive Escherichia coli invade and destroy mucosal epithelial cells. Death occurs as a result of dehydration and electrolyte imbalance.

Bleeding peptic ulcers that are caused by Helicobacter pylori may be the first indication of an ulcer and account for 25% of ulcer deaths, many of which are sudden and unexpected.

Fulminant bacterial peritonitis secondary to acute appendicitis, acute salpingitis, ruptured peptic ulcer, diverticulitis, strangulated bowel, and cholecystitis may cause sudden death. Primary peritonitis may occur postsplenectomy and in patients with splenic hypoplasia. Patients with sickle-cell disease may have anatomical or functional asplenia. The former is due to repeated bouts of infarction leading to autosplenectomy. The latter is due to a defect in opsonization of encapsulated bacteria.

Massive bilateral adrenal hemorrhage with adrenocortical insufficiency may occur as a result of septicemic shock from overwhelming bacterial infection (Waterhouse–Friderichsen syndrome). The most common association is with Neisseria meningitidis septicemia; however, other virulent organisms, e.g., H. influenzae and Pseudomonas species, may also lead to this syndrome.

Fungal Causes of Sudden Death

Sudden death due to fungal infection may occur in an immunocompromised host such as in HIV/AIDS. Organisms include Cryptococcus (meningitis or disseminated disease) and Pneumocystis carinii (pneumonia).

Intravenous drug abusers are susceptible to endocarditis due to fungi such as Candida. These patients are prone to fungal thromboembolism, leading to sudden death.

Sudden death may also be due to a complication of fungal diseases such as fatal subarachnoid hemorrhage complicating actinomycotic meningitis or fatal hemoptysis complicating pulmonary mucormycosis.

Diagnostic modalities include culture of the organism and the histological demonstration of the organisms in tissue. This may be facilitated by special stains such as the periodic acid–Schiff (PAS) or Grocott's methenamine silver stain.

Protozoal Causes of Sudden Death

Fatal cardiac tamponade may occur with intrapericardial rupture of an amebic liver abscess due to Entamoeba histolytica. Fatal amebic meningoencephalitis may be caused by Naegleria fowleri. The organism enters the arachnoid space through the cribriform plate of the nose. There is meningeal hemorrhage with fibrinoid necrosis of blood vessels.

Cerebral malaria does not usually cause sudden death. However, it may be the primary cause of sudden death in nonimmune persons. Susceptible individuals are tourists, business travelers, and sailors. At autopsy, the brain is swollen and may have a “slate gray” color due to the brown-black malarial pigment called hemozoin. Histology reveals petechial hemorrhages as well as intravascular parasitized red cells. Small perivascular inflammatory foci called malarial or Dürck's granulomas may be present. Sudden death in malaria may also be due to rupture of an enlarged spleen. An enlarged spleen is fragile and more vulnerable to rupture. Other infections that may lead to splenic rupture and sudden death are infectious mononucleosis and typhoid.

Sudden death due to cardiac involvement in Chagas disease (Trypanosoma cruzi) occurs in 5–10% of acute cases. The damage to the myocardium causes fatal ventricular tachycardia. Histological examination shows myofiber necrosis with an acute inflammatory reaction. Clusters of organisms may be found within dilated myofibers, resulting in intracellular pseudocysts.

Helminthic Causes of Sudden Death

Clinically occult helminthic diseases such as hydatid disease (Echinococcus granulosus) and neurocysticercosis (Taenia solium) may cause sudden death. In neurocysticercosis death may occur due to epilepsy or raised intracranial pressure. Parasitic cysts containing scolices are present, especially in the subarachnoid space, cortical sulci, and cortical gray matter. Large multilocular cysts (racemose cysts) may be present in the basilar cisterns near the cerebellopontine angle (Figure 5 ).

Figure 5.

Hydrocephalus with basal obliterative, granulomatous cysticercus meningitis. Courtesy of Professor RH Hewlett, University of Stellenbosch.

Isolated cardiac hydatid cyst is an uncommon manifestation and accounts for fewer than 3% of all hydatid disease. Sudden death may be the initial manifestation of the disease. Death may be due to involvement of the left ventricular myocardium or to massive pulmonary embolism.

Autopsy in Cases of Sudden Death due to Infectious Causes

All autopsies must be approached using universal precautionary principles.

In sudden deaths complete autopsy examination is recommended with appropriate tissue and body fluid sampling for special investigations.

Autopsy sampling for microbiological investigations is indicated in the following circumstances: sudden unexpected deaths in children and adults, deaths in immunocompromised patients, deaths in patients with clinically suspected infections, and deaths with organ changes of infection. The problems encountered with autopsy microbiological testing are contamination during procurement of the sample because of poor technique or due to the postmortem spread of commensals.

To prevent false-positive postmortem blood cultures the following should be observed: the body should be refrigerated as soon as possible; and movement of the body should be limited to decrease the possibility of postmortem bacterial spread. An aseptic technique should be used to collect the sample, which should be stored and transported in the correct medium and temperature.

Close liaison with the microbiology and virology laboratories is important to guide collection, preservation, transport, and evaluation of specimens. This is particularly important in cases where there are positive cultures with negative histological findings. Sampling at multiple sites and determining the antibiotic sensitivities may be helpful in determining the significance of positive cultures. The finding of a “pure” as opposed to “mixed” culture helps to determine the significance of the findings. The type of organism in relation to the site where it was cultured also helps to differentiate contaminants from significant positive cultures.

Relevant special techniques should be used by the pathologist in order to improve the diagnostic yield in infectious diseases (Table 5 ).

Table 5.

Special techniques used to demonstrate infectious agents

Organism	Special technique	Comment
Viruses	Hematoxylin & eosin, antibody probes, culture and DNA probes	Intranuclear and/or cytoplasmic inclusions, giant cells
Chlamydia	Giemsa, culture	Necrotizing granulomas with stellate abscesses
Bacteria	Gram stain, silver stain, acid-fast stain, culture, DNA probes	Polymerase chain reaction and ligase chain reaction for mycobacteria
Fungi	Periodic acid–Schiff, silver stain, Giemsa, culture	Mucicarmine for capsule of cryptococcus
Protozoans	Giemsa, periodic acid–Schiff, DNA probes
Helminths	Modified acid-fast stain	In bilharzia, acid-fastness is concentrated in the spine of the egg

In a small group of cases (so-called negative autopsies) no obvious cause of death is apparent after detailed initial external and internal examination. The incidence of negative autopsies is 5%–10%; this figure improves to about 5% when special tests such as postmortem chemistry and microbiology are carried out.

Conclusion

Infectious agents are not a common cause of sudden death. Even in cases with little or no morphological changes, investigation of appropriate autopsy samples by recently developed laboratory techniques may prove invaluable and shed light on the cause of death.

See Also

CHILDREN | Sudden Natural Infant and Childhood Death SUDDEN NATURAL DEATH | Cardiovascular SUDDEN NATURAL DEATH | Central Nervous System and Miscellaneous Causes