530 CHAPTER 44 Respiratory infection: viral Viral pneumonia: overview \200 Viral upper respiratory tract infections are common, but typically self- limiting, and are usually managed in the community. Viral pneumonia is much less common but is more serious a nd usually requires hospitalization. Viral pneumonia in the immunocompetent is rare and typ ically affects children or the elderly; in \202 uenza strains are the commonest cause in a dults Viruses may cause serious respiratory infection in the immunocompro- mised (particula rly patients with depressed T-cell function, e.g. following organ transplantation). CMV is the commonest serious viral pathogen that affects immunocompromised patients. In \202 uenz a, parain \202 uenza, RSV, measles, and adenovirus may also cause pneumonia in the immuno- compromised, although diagnosis of these viruses is dif \201 cult and infection is common ly undetected The clinical and radiological features of viral pneumonia are non- speci \201 c. Worsening cough and breathlessness following an upper respi- ratory tract infection suggest the development of pneumonia; wheeze may accompany bronchiolitis. CXR typically sh ows non-speci \201 c diffuse interstitial in \201 ltrates, and hypoxia may occur. Seconda ry bacterial infec- tion may complicate viral pneumonia A variety of diagnostic techniques are available, including viral culture and immuno \202 uorescence staining (e.g. of BAL \202 uid) and serology Treatment consists of supportive care and in some cases antivirals. Infection with certain viruses may require isolation. Treat secondary bacterial infection w ith antibiotics Speci \201 c features of the common and/or important viruses are noted in the remainder of the chapter. This page intentionally left blank 532 CHAPTER 44 Respiratory infection: viral In \202 uenza: diagnosis \200 Commonest cause of viral pneumonia in immunocompetent adults. It is transmitted via respira tory secretions and is extremely contagious. Seasonal in \202 uenza is very well recognize d in the UK, particularly during the winter months, and recently outbreaks of H5N1 avian in \202 uenza have occurred in many countries, raising fears of the development of sustained human-to-human transmission and a new global pandemic Three pathogenic serotypes: A, B, an d C. Type A causes more severe disease and occurs in annual epidemics and intermittent pand emics. Types B and C cause epidemics The surface antigens haemagglutinin and neuraminidase determine in \202 uenza serotype. Genetic mutations may result in antigenic shifts (major genetic rearrangements between strains, associated with pan- demics) and antigenic drifts ( more minor genetic variations associated with epidemics). Genetic rearrangement of virus oc curs in animal and bird reservoirs, and the virus may then be transferred to humans Seasona l in \202 uenza may affect previously well individuals, although it occurs more commonly i n the elderly, particularly in the setting of chronic heart or lung disease or immunocompro mise. Pandemic in \202 uenza differs in that it is also associated with signi \201 cant m ortality in younger adults. Regularly updated information on seasonal, avian, and pandemic in \202 uenza is available from the Health Protection Agency website: http://www.hpa.org.uk/infections/topics_az/in \202 uenza Additional guidelines are available for the management of suspected in \202 uen za in the setting of a pandemic with UK Pandemic Alert Level 2 (cases of pandemic in \202 uenza identi \201 ed in UK): http://www.brit-thoracic.org.uk/PandemicFlu.html http://www.d h.gov.uk/en/PandemicFlu/index.htm Clinical and laboratory features Incubation period typica lly 1 \200\2234 days; adults contagious for 7 days and children for 21 days from illness on set. The clinical picture following infection is variable and may be in \202 uenced in par t by the in \202 uenza subtype. Features include: \200 \200 Asymptomatic infection \200\230Flu \200\231 (acute onset of fever, cough, headache, coryza l symptoms, myalgia, sore throat) Complications include: \200 \200 Bronchitis/bronchiolitis Primary in \202 uenza viral pneumonia (onset typically within 48 h of initial fever; cough dry or productive, haemoptysis may occur, bilateral crackles and/ or wheeze; may progress very rapidly to respi- ratory failure and death; described in major ity of patients infected with avian in \202 uenza H5N1, often associated with lymphopenia, thrombocytopenia, abnormal liver function, and multi-organ failure) INFLUENZA: DIAGNOSIS 533 Secondary bacterial pneumonia (signi \201 cantly more common than viral pneumonia; onset t ypically 4 \200\2235 days after initial fever, during early convalescence, although may occ ur earlier; pathogens include S. pneumoniae, S. aureus \200\224particularly associated with lung abscess \200\224and H. in \202 uenzae; mixed bacterial/viral pneumonia may occur) Ga strointestinal symptoms (e.g. watery diarrhea; more frequently described during avian in \202 uenza A H5N1 than seasonal infection) Otitis media (particularly in children), conjunc tivitis; rarely parotitis Myositis (creatine kinase may be elevated; rarely myoglobinuria w ith renal failure) Neurological (encephalitis, acute necrotizing encephalopathy, trans- ver se myelitis, Guillain \200\223Barr syndrome all rare; Reye \200\231s syndrome with enceph alopathy and fatty liver following aspirin use is well described in children and adolescent s) Cardiovascular (ECG abnormalities common, myocarditis or peri- carditis rare). \200 Imaging \200 CXR typically shows bilateral mid-zone interstitial in \201 ltrates in primary viral pneum onia, although focal consolidation is also well described. Lobar consolidation occurs in se condary bacterial pneumonia. Differential diagnosis of \200\230 \202 u-like \200\231 illness includes adenovirus, RSV, rhinovirus, parain \202 uenza, Chlamydia pneumoniae, Legionella, Mycoplasma, and S. pneum oniae. A very high fever is said to favor a diagnosis of in \202 uenza. Consider SARS (p 5 42) in patients with an appropriate travel history. Diagnosis is often suggested by knowled ge of a local outbreak. Diagnostic investigations include: \200 Virology (not routinely required if pandemic established with wide- spread infection across the UK \200\224Alert Level 4 \200\224when diagnosis will be clinical) \200 Presentation <7 days after illness onset: nose and throat swabs in virus transportation med ium (for direct immuno \202 uorescence, ELISA, virus culture, and/or PCR) Presentation >7 days after illness onset: \200\230acute \200\231 serum and subse- quently \200\230convale scent \200\231 serum after 7 days (for in \202 uenza serological testing) Bacteriology (in patients with in \202 uenza-related pneumonia) \200 \200 \200 Blood culture Pneumococcal and Legionella urinary antigen Sputum M,C&S (if purulent sputum and either no prior antibiotics or failure to respond to empirical antibiotics) \200\230Ac ute \200\231 serum and subsequently \200\230convalescent \200\231 serum after 7 days for i n \202 uenza/other agents serological testing 534 CHAPTER 44 Respiratory infection: viral In \202 uenza: management Severity assessment \200 \200 Patients with uncomplicated in \202 uenza do not require admission For in \202 uenza-rela ted pneumonia, a CURB-65 score (p 424) of \211 3 indi- cates severe pneumonia and a high r isk of death; patients with a score of 0 or 1 may be considered for home treatment Bilatera l CXR in \201 ltrates consistent with primary viral pneumonia should be considered as seve re pneumonia, irrespective of CURB- 65 score. Infection control \200 Outside the setting of a UK pandemic, most suspected cases of in \202 uenza are likely to be seasonal, although H5N1 avian in \202 uenza should be seriously considered in patients with: \200 \200 Fever or history of fever and breathlessness or cough and travel in the previous 2 weeks to a region known to have cases of H5N1 in birds (e.g. China, Egypt, Indonesia, Thailand, Vie tnam, many more; see Health Protection Agency website on p x for updated list) and close co ntact (within 1 m) with live or dead poultry (not meat or eggs) or other H5N1-con \201 rme d animal (e.g. pigs) within 7 days of symptom onset Consider also in patients with febrile respiratory illness and contact with sick, dying, or dead poultry in absence of travel hist ory, and in health care and laboratory workers with exposure to con \201 rmed or possible avian in \202 uenza cases In such cases, the patient should be assessed either at their home or in a hospital side-ro om, with both patient and staff wearing surgical masks and staff wearing gown and gloves. I mmediately inform local Health Protection Unit, as well as hospital infection control and o ccupational health. If hos- pitalization is required, patients should be in strict respirat ory isolation, preferably in a negative pressure room (although patients should not be tran sferred for this reason alone), and staff should wear high \201 ltra- tion mask (FFP3), g own, gloves, and eye protection (consider also cap and plastic apron, depending on situatio n). Mark all laboratory samples as \200\230high risk \200\231 and inform local laboratory of the sample status. Treatment \200 Supportive care: oxygen, intravenous \202 uids, nutritional support. Consider ITU/HDU adm ission for patients with one of more of: primary viral pneumonia; CURB-65 score of 4 or 5; PaO2 <8 Kpa despite high- \202 ow oxygen; progressive hypercapnia; pH <7.26; septic shock. NIV may be used for patients with COPD and decompensated type II respiratory failure, alth ough infection control measures should be in place and protective equipment worn by staff t o minimize any spread of infection from respiratory droplets INFLUENZA: MANAGEMENT 535 Antiviral treatment with neuraminidase inhibitors is indicated for patients with an in \202 uenza-like illness and fever >38 C within 48 h of symptom onset; consider also treati ng immunocompromised or very elderly patients in the absence of fever, and severely ill or immunocom- promised patients if >48 h from disease onset. Treat with oseltamivir (Tami \202 u) 75 mg bd for 5 days (75 mg od if creatinine clearance <30 ml/min); anti-emetics may be needed for nausea. Antivirals appear to reduce illness duration (by 1 day), hospitaliza tion, and subsequent antibiotic requirements; possible effects on mortality have not been a dequately studied, and the ef \201 cacy of neuraminidase inhibitors in pan- demic in \202 uenza is unknown. The neuraminidase inhibitor zanamivir may be given intravenously (e.g. f or ventilated patients), but its effectiveness in this situation is unproven. Antiviral pro phylaxis may be considered for health care workers caring for patients with suspected avian in \202 u- enza, as well as the patient \200\231s household contacts Treat in \202 uenza -related pneumonia with antibiotics according to severity, e.g. oral co-amoxiclav, a tetrac ycline (e.g. doxycycline), or a macrolide if non-severe; intravenous co-amoxiclav or cefuro xime or cefotaxime together with a macrolide if severe. Outcome Uncomplicated in \202 uenza typically resolves within 7 days, although cough and m alaise may persist for several weeks. The reported mortality from primary in \202 uenza vi ral pneumonia is >40% and up to 24% from sec- ondary bacterial pneumonia. Vaccination \200 The in \202 uenza inactivated vaccine is modi \201 ed annually based on recent viral stra ins, and provides partial protection against in \202 uenza illness, hospitalization, and d eath. Vaccination if age >65, chronic comorbidity, nursing home residents, or health worker s. Vaccination will not protect against H5N1 avian in \202 uenza, but may make simultanous co-infection with human and avian in \202 uenza less likely, and so reduce the likelihood of viral genetic re-assortment Administration of oseltamivir 75 mg od to high-risk individ uals throughout periods of exposure may also prevent infection Live attenuated in \202 uen za vaccines are currently under investigation. 536 CHAPTER 44 Respiratory infection: viral Cytomegalovirus pneumonia Epidemiology \200 CMV is the commonest serious viral pathogen in the immunocom- promised, and is a particular problem following transplantation, where prophylaxis is now widely used Individuals are de scribed as \200\230seropositive \200\231 for CMV if they have evidence of IgG antibodies i ndicating latent infection following previous expo- sure; seropositivity increases with age . Infection in transplant recipients results from either transmission from a CMV-positive d onor to a CMV antibody-negative recipient (via the organ or a blood transfusion) or reactiv ation of latent CMV in a seropositive recipient as a result of immunosuppression Infection occurs most frequently during the \201 rst 4 months following organ or bone marrow transp lantation, corresponding to the period of maximal T-cell suppression. Graft-versus-host dis ease increases the risk of CMV infection. Clinical and laboratory features \200 \200 \200\230Flu-like \200\231 symptoms in immunocompetent patients Symptoms of CMV pneumonia i n the immunocompromised are non- speci \201 c: fever, dry cough, dyspnoea, and malaise Ext rapulmonary manifestations of CMV infection (e.g. gastro-oesopha- gitis; hepatitis) may sug gest the diagnosis Hypoxia may occur. Leucopenia, thrombocytopenia, and abnormal liver func tion tests are characteristic. Imaging \200 CXR typically bilateral diffuse interstitial in \201 ltrate, although lobar consolidation and localized haziness also described; can be normal. A nodular in \201 ltrate may suggest co-infection with Aspergillus CT features include localized or diffuse ground-glass and no dular shadowing that may progress to airspace consolidation. Diagnosis Antibody tests are used to estimate risk following transplanta- tion, but diagnos is of active disease requires evidence of either viraemia (by antigen or PCR testing of blo od) or tissue invasion (by biopsy). A wide range of diagnostic tests are available, and the choice of tests varies between centers \200\224discuss with your local virologist. The nat ure of the transplant and immunosuppression also in \202 uence the interpretation of test results. Methods include: \200 Early antigen \202 uorescence test on BAL \202 uid (high sensitivity, low speci- \201 city) Qualitative PCR on blood or BAL \202 uid (highly sensitive, but unable to differen tiate between latent and replicating CMV; negative result practi- cally excludes the diagno sis, positive result is unhelpful) CMV antigenaemia on blood (rapid, differentiates between latent and replicating virus) Quantitative PCR on blood or BAL \202 uid (rapid, differen tiates between latent and replicating virus). CYTOMEGALOVIRUS PNEUMONIA 537 Indirect immuno \202 uorescence with monoclonal antibodies to CMV in BAL \202 uid (rapid , highly sensitive, and speci \201 c) Histology of lung tissue from transbronchial or surg ical biopsies (dem- onstrate CMV inclusion bodies \200\224the \200\230owl \200\231s eye \200\231 appearance \200\224within infected cells; considered gold standard investigation). In some cases a de \201 nitive diagnosis is not possible, and treatment is empirical. Trea tment Ganciclovir 5 mg/kg IV bd for 2 \200\2234 weeks (side-effects include neutropenia, an emia). Consider additional treatment with anti-CMV hyperimmune globulin or prolonged oral v alganciclovir in cases of severe or relapsed disease. Foscarnet 60 mg/kg tds for 2 \200\223 3 weeks is an alternative to ganciclovir for resistant cases, but toxicity (nephrotoxicity, metabolic disturbance) can limit treatment. Complications \200 Opportunistic infection (e.g. PCP, aspergillosis) due to further suppres- sion of T-cell fu nction by the CMV infection itself Increased risk of organ rejection, as allografts are mor e susceptible to CMV infection than native organs. Outcome The reported mortality from CMV pneumonia varies, although may be as high as 85%. R elapse occurs in up to one-third of patients. 538 CHAPTER 44 Respiratory infection: viral Varicella pneumonia \200 Pneumonia occurs in a small proportion of adults with chickenpox or shingles. Risk factors for its development include smoking, increased number of skin spots (>100), pregnancy (thir d trimester), steroid treat- ment, and immunocompromise There is typically a history of rec ent exposure to a contact infected with chickenpox or shingles. Chest symptoms tend to occu r several days after the onset of rash (erythematous macules progressing to papules and the n vesicles), although rarely may precede the rash. Cough and breathlessness are common, and pleuritic pain and haemop- tysis may occur CXR typically shows a diffuse small nodular in \201 ltrate; hilar lymphade- nopathy and pleural effusions may uncommonly occur. Nodules m ay subsequently calcify and persist Multi-organ involvement may occur Diagnosis is usually suspected on the basis of the history of exposure, presence of rash, and CXR features. Cyto logical examination of smears from skin lesions, serology, or viral culture or PCR on BAL \202 uid may con \201 rm the diagnosis Treatment of varicella pneumonia is with early adm inistration of aci- clovir 10 \200\22312.5 mg/kg, IV tds for 7 \200\22310 days. Aciclovir i s not licensed for use in pregnancy, but does not appear to be associated with increased fe tal abnormalities and the bene \201 ts of treatment almost certainly outweigh any risk. Va ricella is very infectious until lesions enter the \200\230crusting \200\231 stage; in-pat ients should be isolated. Extracorporeal mem- brane oxygenation/life support has been used successfully in individuals with fulminant respiratory failure. Consider early administrati on of vari- cella-zoster immune globulin for immunocompromised and pregnant patients expose d to varicella Most cases resolve spontaneously, but a minority progress to respira- tory f ailure and death. Mortality may be signi \201 cantly higher in pregnancy. \200 MEASLES 539 Respiratory syncytial virus \200 Very common cause of bronchiolitis and pneumonia in children. Role in adult respiratory dis ease is more signi \201 cant than previously appreci- ated, and infection often goes unrec ognized Adult infection occurs particularly in the setting of underlying cardiac or respira tory disease or malignancy; outbreaks affecting adults in hos- pitals and nursing homes als o occur. RSV may be a relatively common viral cause of pneumonia in patients who have recen tly undergone bone marrow transplantation Bronchoscopy with BAL is often diagnostic: detect ion of RSV antigen in BAL \202 uid has a sensitivity of nearly 90%. PCR-based diagnostic techniques and serological testing may have a role Bacterial superinfection may be a freque nt complication Treatment is principally supportive. Role of aerosolized ribavirin and ster oids in the treatment of severe disease in adults is unclear. Reports of successful outcome s in bone marrow transplant recipients following treatment with ribavirin and immunoglobuli n. \200 Measles \200 Very rare in adults. Bronchiolitis and pneumonia affect 50% of patients infected with measl es and are a common cause of mortality in children Symptoms of fever and upper respiratory tract infection are followed by a diffuse maculopapular rash. Leucopenia is common CXR may show reticulonodular in \201 ltrates, hilar lymphadenopathy, and pleural effusions Seconda ry bacterial infection is common Treatment is supportive. Treat secondary bacterial infecti on with antibiotics. \200 540 CHAPTER 44 Respiratory infection: viral Hantavirus pulmonary syndrome \200 First described following an outbreak in the south-western USA in 1993. Several different h antaviruses (e.g. Sin Nombre virus) have been associated with this syndrome. Previously des cribed hantavirus-associ- ated diseases occurred more commonly in Scandinavia and north- ea stern Asia, and tended to cause haemorrhagic fever and renal failure with relative sparing of the lung Very rare, and affected individuals are almost exclusively from the USA, partic ularly from the Four Corners Region where Arizona, Colorado, Utah, and New Mexico meet Dise ase develops following inhalation of aerosolized viruses from rodent feces, urine, or saliv a Typically affects previously well young adults Common presenting symptoms are fever, chil ls, cough, myalgia, and gastrointestinal symptoms, such as vomiting and abdominal pain. Bre athlessness occurs later in the disease course, and is often quickly followed by respirator y failure and the development of ARDS. Shock may occur and is associated with a poor progno sis Laboratory testing classically reveals neutrophilia and thrombocyto- penia, sometimes r enal impairment and mildly abnormal LFTs CXR typically shows initially bilateral basal in \201 ltrates that progress to involve all regions of the lung; a minority are normal Diagno sis may be con \201 rmed using serology, PCR for the virus, or by detection of viral antig en using immunochemistry Treatment is supportive within an intensive care unit. It is uncle ar if person-to-person transmission occurs, and patients should be in respiratory isolation . Intravenous ribavirin is commonly administered, although it is unclear if this improves o utcome Mortality 30 \200\22350%, with death usually occurring within several days of presen tation \200 This page intentionally left blank 542 CHAPTER 44 Respiratory infection: viral Severe acute respiratory syndrome (SARS): epidemiology and pathophysiology This rapidly pro gressive acute respiratory illness was \201 rst recognized in November 2002 in the Guangd ong Province of China. By late February 2003 it had spread internationally. It was termed S ARS by the World Health Organization (WHO), whose involvement was (in association with heal th authorities from the United States, Canada, Singapore, Hong Kong, and other Asian countr ies) to determine an etiology, establish infection control measures to prevent further spre ad, establish a laboratory test for diagnosis, and evaluate treatments. Epidemiology Cases of SARS were \201 rst recognized in the Guangdong province of China in November 2002, wit h 792 cases reported by February 2003. This \201 rst outbreak mainly affected health care workers and their contacts. The disease spread to Hong Kong via a Guangdong province physi cian, who infected individuals in a Hong Kong hotel lift. The disease rapidly spread to Sin gapore, Thailand, Vietnam, and Canada via travelers from Guangdong province and Hong Kong. Case numbers fell by mid May 2003, and by July 2003 the worldwide epidemic had ended. Furth er cases have subsequently been reported. An isolated case of laboratory-acquired SARS was reported in Singapore in September 2003. A further laboratory outbreak occurred in March 20 04, with serologically proven infection in four individuals working at the same institute i n Beijing. A total of 8098 cases were reported to the WHO by August 2003, with 774 deaths, giving a ca se fatality rate of 9.5%. The fatality rate for those aged \211 60 was 43%. 29 countries o n all \201 ve continents were affected. 83% of the worldwide cases were in China and Hong Kong. No deaths occurred in the United States or the UK. 41 deaths (of 251 cases) were in Canada. Case de \201 nition The WHO de \201 ned criteria for those presenting with the di sease after July 2004: \200 \200 Fever >38*C plus One or more symptom of lower respiratory tract illness (cough, dif \201 c ulty breathing, shortness of breath) plus Radiographic evidence of lung in \201 ltrate con sistent with pneumonia or ARDS, or autopsy \201 ndings consistent with the pathology of p neumonia or ARDS without identi \201 able cause plus No alternative diagnosis to explain t he illness Laboratory case de \201 nition \200 \200 A person with symptoms or signs suggestive of SARS plus Positive laboratory \201 ndings f or SARS-CoV based on one or more of: \200 \200 \200 PCR positive for SARS-CoV Seroconversion by ELISA or IFA Virus isolation Testing should only be undertaken in a national or regional reference labo- ratory, as per WHO recommendations. SARS: EPIDEMIOLOGY AND PATHOPHYSIOLOGY 543 Pathophysiology A novel, previously undescribed coronavirus (SARS- CoV) is thought to be th e causal agent. It is still to be ascertained whether microbiological and other cofactors e nhance severity or transmissibility. The complete genetic sequence of the SARS-CoV has now been deter- mined. It is currently thought that animals act as the main reservoir. SARS is mostly spread by large droplets and person-to-person contact. There have been no re ports of food- or water-borne transmission. However, SARS-CoV is shed in large quantities i n stool, and profuse watery diarrhea is a common symptom. Nosocomial transmission of SARS-C oV has been a striking feature in most outbreaks. The use of aerosol gen- erating procedure s (endotracheal intubation, nebulization, bronchoscopy) may amplify transmission. Lung post mortem studies show diffuse alveolar damage, secondary bacterial pneumonia, and i nterstitial giant cell and macrophage in \201 ltration. Pathological \201 ndings similar to those of bronchiolitis obliterans are recog- nized. There are no speci \201 c diagnost ic features. Incubation period is 2 \200\22310 days prior to the onset of the \201 rst sy mptom, which is typically fever. 544 CHAPTER 44 Respiratory infection: viral SARS: clinical features and management Clinical features The disease is a two-stage illness , commencing with a prodrome of fever (>38*C), with or without rigors, with non-speci \201 c systemic symptoms, e.g. malaise, headache, and myalgia. The respiratory stage of the illness starts 3 \200\2237 days after the prodromal phase with dry cough and breathlessness. Progression to respiratory failure needing ventilation is we ll recognized. Up to 70% of patients develop large volume watery diarrhea without blood or mucus. Destruction of lung tissue is thought to result from an excessive immune response to the vi rus, rather than from the direct effects of virus replica- tion. Peak viral load is at day 12 \200\22314 of infection, with virus shed not only in respiratory secretions, but in fece s and other body \202 uids. Retrospectively devised but non-validated scoring systems show that the presence of cough, myalgia, diarrhea, and rhinorrhoea or sore throat are 100% sensitive and 76% speci \201 c at identifying a patient with SARS. Children experience a milder form of the disease, with a low death rate. Investigations The illness is a symptom complex and the case de \201 nition is broad. Diagnosis is made on t he basis of the clinical syndrome and absence of positive bacteriology and virology. SARS i s a diagnosis of exclusion. Recommended investigations in a suspected case include \200 Blood tests \200 White blood count is normal or reduced, with a low total lympho- cyte count (in 98% in the Hong Kong case series) Leucopenia and thrombocytopenia are also recognized, with raised cre atine kinase (CK) and alanine transferase (ALT). A raised lactate dehydrogenase (LDH) is as sociated with a poorer outcome CXR ranges from normal to diffuse bilateral interstitial in \201 ltrate. Areas of focal co nsolidation, initially peripherally and lower zone in distribu- tion, are also described. C avitation, hilar lympadenopathy, and pleural effusion are uncommon at presentation. CT may reveal areas of interstitial in \201 ltrate, ground-glass opacities, and interlobular sept al thickening in those with a normal CXR. Spontaneous pneumothorax, pneumomediastinum, subp leural \201 brosis, and/or cystic changes can occur in later stages SARS-CoV can be detec ted by RT-PCR (sensitivity 70%, dependent on specimen type and duration of illness). Useful specimens include naso- pharyngeal aspirate, throat swab, urine, and feces. An initial pos itive result on PCR must be con \201 rmed by another clinical sample, re-extracting and te sting the original sample, and using assays that target different parts of the genome. Howe ver, identi \201 cation of sero- conversion on a whole virus immunoassay remains the gold standard for the retrospective virological con \201 rmation of the disease. The anti- body response peaks at 10 \200\22314 days after the onset of fever. Agreement has been reached between international agencies to share specimens and laboratory data to develop a diagnost ic test as soon as possible. Work to standardize PCR and ELISA testing for the SARS virus i s ongoing SARS: CLINICAL FEATURES AND MANAGEMENT 545 Treatment \200 There is no speci \201 c treatment for SARS other than general supportive care. No RCT tre atment data exists Some patients have been treated with oseltamivir and/or intravenous riba virin. Immunoglobulin, anti-TNFA, highly active retroviral therapy (HAART), anti-platelet a gents, and convalescence serum from SARS patients have all been all tried Patients treated with Kaletra (400 mg ritonivir and 100 mg lopinavir) with ribavarin for 14 days had a low er incidence of ARDS and death, and this combination should be considered early for SARS pa tients, ideally in a randomized controlled trial Interferon B limits SARS-CoV replication i n vitro, and patients treated with interferon alfacon-1 with corticosteroid had a better cl inical course, with lower death rates Steroids lead to reduced fever, and improved oxygenat ion and CXR appearance, but do not alter need for ITU, or the death rate at 3 weeks. Some d ata suggest that high dose IV methylprednisolone (500 mg qds for 3 \200\2236 days) may be l ife-saving for patients with deterio- rating radiographic consolidation and increasing oxyg en requirements ( \200\230critical SARS \200\231) A series from Toronto showed a trend towa rds worsening outcome in those treated with ribavirin, due to elevated transaminases and ha e- molysis. There are no in vitro data to show any anti-SARS virus activity of ribavirin Ex perimental animal models show reduced viral replication with pegylated interferon A, and hu man studies using interferon and cortico- steroids have shown no adverse effects Some studi es show bene \201 t from therapy with high-dose methylpred- nisolone given in the later st ages of the illness; however, randomized placebo-controlled trials are awaited Vaccinations are being developed Hospital admission Nosocomial transmission of SARS-CoV has been a striking feature in most outbreaks. Infected and suspected cases should be managed in negative pressure side rooms. Full protective clothing, including protective eye wear and face masks, are recommended for all visitors and health care workers. The use of aerosol generating proce- dures should be avoided where possible. Prognosis Older age is associated with a poorer outcome. Diabetes and other comorbid illness are independent risk factors for death. Prevention focuses on av oidance of exposure and effective infection control measures. Closure of hospitals and scho ols in affected areas and the use of quarantine measures helped to limit the spread of the disease in a number of countries. Further information Peiris JSM, Yuen KY et al. The severe acute respiratory syndrome. NEJM 2003; 349: 2431 \200\22341 WHO website for continuously updated information: www.who.int/csr/sars/en Diagnosis and pharmacotherapy of severe acute respiratory syndrome: what have we learned? E RJ 2004: 24: 1025 \200\22332. This page intentionally left blank 547 Chapter 45 Sarcoidosis Etiology and pathology 548 Chest disease: clinical features 550 Chest disease: management 5 52 General management 554 Extra-thoracic disease 1 556 Extra-thoracic disease 2 558 548 CHAPTER 45 Sarcoidosis Etiology and pathology De \201 nition \200 A multisystem in \202 ammatory disorder of unknown cause, likely resulting from the interp lay of environmental and genetic factors Characterized by non-caseating granulomata and CD4 Th1-biased T-cell response in affected organs Commonly involves the respiratory system, bu t can affect nearly all organs 50 \200\22360% of people have spontaneous remissions; others may develop chronic progressive disease Etiology Incidence varies with population studies, from 5 to 100/100 000, according to geog raphic distribution. UK incidence is about 5 \200\22310/100 000. Commoner in African-Americ ans, West Indians, and the Irish. Commonly presents between ages of 20 and 40. Unusual in c hildren and the elderly. Typically more aggressive disease in Black populations than in Cau casians \200\224especially with skin disease, peripheral lymphadenopathy, bone marrow, and liver involvement; higher relapse rates and worse long- term prognosis Genetics Familial and ethnic clustering of cases suggest a genetic predispo- sition. Siblin gs of an affected person have a 5x increased risk of developing sarcoidosis. Best evidence of HLA association comes from recent large multicentre ACCESS study, showing HLA-DRB1*0301 is associated with susceptibility to disease in Blacks and Whites. Also a genome-wide scan for susceptibility genes in familial sarcoidosis has been performed, pointing to a locus on chromosome 5 in African-Americans and chromosome 6 in German Caucasians. Pathology Sarcoid osis is caused by an immunological response: \200 Unknown antigenic stimulus triggers CD4 (helper) T-cell activation and expansion. This resp onse is exaggerated and Th1-biased, with resultant interferon gamma and IL-2 production fro m these T-cells Activated T cells proliferate and release mediators, attracting additional in \202 ammatory cells with concomitant macrophage activation and aggre- gation This leads to immune granuloma formation, which is enhanced by inter- feron gamma Granulomata themsel ves cause increased local \201 broblast stimulation and hence \201 brosis Metabolic act ivity of macrophages causes raised ACE (angiotensin- converting enzyme) levels in serum, lu ng tissue, and bronchoalveolar \202 uid. Increase in T-cell activity causes B-lymphocyte stimulation, which can cause raised serum immunoglobulins and immune complexes In most pati ents, response resolves over 2 \200\2235 years Delayed-type hypersensitivity reactions are depressed in sarcoidosis. This is thought to be due to the migration of lymphocytes to the active com- partment (lungs), with resultant pe ripheral blood lymphopenia. Seen as a decreased response to tuberculin, mumps virus, and Ca ndida albicans antigens. This is not thought to be clinically signi \201 cant. etiology AND PATHOLOGY 549 Sarcoid-like reactions are reported in association with malignancy and also in HIV patients starting on antiretroviral therapy (very rare). Non-caseating pulmonary granulomas are fou nd, but there are no other symptoms or signs of sarcoidosis. Differential diagnosis of granuloma on lung biopsy \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 \200 Sarcoidosis Tuberculosis Extrinsic allergic alveolitis Wegner \200\231s granulomatosis Prim ary biliary cirrhosis Granulomatous orchitis Langerhans cell histiocytosis Leprosy Tertiary syphilis Brucellosis Berylliosis Silicosis Hypogammaglobulinaemia Fungal infections \200 \224coccidioidomycosis Schistosomiasis Cat scratch fever Lymphoma Giant cell arteritis Poly arteritis nodosa Takyasu \200\231s arteritis Crohn \200\231s disease De Quervain \200\231s thyroiditis Further information Iannuzzi MC. Advances in genetics of sarcoidosis. Proc Am Thorac Soc 20 07; 4: 457 \200\22360. Schurmann M, Lympany PA et al. Familial sarcoidosis is linked to the major histocompatabili ty complex region. Am J Respir Crit Care Med 2000; 162: 861 \200\2234. Schurmann M, Bein G et al. HLA-DQB1 and HLA-DPB1 genotypes in familial sarcoidosis. Respir Med 1998; 92: 649 \200\22352. 550 CHAPTER 45 Sarcoidosis Chest disease: clinical features More than 90% of patients with sarcoidosis have thoracic i nvolvement, with an abnormal CXR. Pulmonary sarcoidosis can be an incidental CXR \201 ndi ng in approximately 30% of patients. There is spontaneous remission in two-thirds and 10 \200\22330% have a chronic course. Clinical features There are probably at least 2 distinct clinical courses: \200 L fgren \200\231s syndrome Mild acute disease, which is usually non-progres- sive. Presents with fever, bilateral hilar lymphadenopathy, erythema nodosum, and arthralgia. Occurs particularly in Caucasians. Has a good prognosis and resolves comple tely and spontaneously in 80% within 1 \200\2232 years. A minority may develop lung disease Persistent progressive in \201 ltrative lung disease Hilar/mediastinal lymphadenopathy May be asymptomatic or cause cough or chest pain. Often b ilateral and symmetrical, but can be unilateral and asymmetrical. Can be associated with sy stemic symptoms of malaise and arthralgia, which are helped by non-steroidal anti-in \202 ammatory drugs. Benign course. Important to exclude other causes of lymphadenopathy, such as TB and lymphoma. May need HRCT and lymph node aspirate or biopsy. Does not require systemic steroid treatment. Stage I: 85% resolve spontaneously over 2 years, 15% develop lung in \201 l- trates. The a verage time for bilateral hilar lymphadenopathy resolution is 8 months Interstitial lung in volvement May be asymptomatic or cause morbidity and mortality, with dyspnoea, cough, chest ache or frank pain, malaise, fatigue, and impaired quality of life. Rarely have crackles o r clubbing on examina- tion. Pulmonary in \201 ltrates on CXR. Can return to normal over t ime, or progress to \201 brosis and respiratory failure. Lung function tests may be norma l, or may show a restrictive defect with reduced transfer factor. Differential diagnosis Ot her interstitial lung disease, malignancy, infection. Radiological classi \201 cation of thoracic sarcoidosis Stage 0 Stage I Stage II Stage III Stage IV Normal Hilar lymphadenopathy Hilar lymphadenopathy and parenchymal in \201 ltrate Parenchy mal in \201 ltrate Fibrosis CHEST DISEASE: CLINICAL FEATURES 551 Seeing a patient with possible sarcoidosis in clinic \200 Make diagnosis \200\224clinical ly, HRCT histology \200 Assess extent/severity/presence of extrapulmonary involvement \200\224 CXR, PFT, ECG, eyes, rash, renal function, serum calcium, liver function, immunogl obulins, and ACE (latter two can be raised in active sarcoidosis) Stable or progressive? \200\224CXR, PFT (VC 9 KCO), oximetry, ACE, urea (if renal involvement) Treatment? Differential diagnosis of bilateral hilar lymphadenopathy on CXR \200 \200 \200 \200 \200 \200 \200 Sarcoidosis Tuberculosis Lymphoma Coccidioidomycosis and histoplasmosis Leukemia Berylliosi s Hypogammaglobulinaemia and recurrent infections. Further information Judson MA, Baughman RP et al. Two year prognosis of sarcoidosis: the AC CESS experience. Sarcoidosis Vasc Diffuse Lung Dis 2003; 20: 204 \200\22311. 552 CHAPTER 45 Sarcoidosis Chest disease: management Diagnosis is based on a characteristic clinical picture, plus: \200 \200 \200 Histological evidence of non-caseating granuloma in any tissue Characteristic picture on im aging (thoracic HRCT scan or gallium scan) Lymphocytosis on bronchoalveolar lavage (BAL) Other diseases capable of producing similar clinical and histological picture, particularly tuberculosis and lymphoma, should be excluded. Investigations \200 