Case

1
Case 2

• 54 year old white male admitted in transfer from
  OSH for further eval/management of hypoxia
• PMH
• Wolff-Parkinson-White s/p ablation
• Chronic hepatitis C
• Arthritis
• Anxiety/depression

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Case 2

• Chronic HCV diagnosed 6/2002 secondary to slight
  ? LFTs
• Referred to NCBH ID for further management 8/2002
• HCV genotype 1a
• HCV VL 2 x 106
• Biopsy 9/9/02 mild periportal chronic
  inflammation and piecemeal necrosis early
  fibrosis
• Self-started PEG IFN/RIB 10/4/2002

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Case 2 Presentation

• Reports development of progressive SOB symptoms
  about the time of initiation of HCV therapy
• Symptoms of DOE and non-productive cough
  persisted
• Evaluated by PCP 10/28/02 and placed on
  azithromycin and steroid taper
• Symptoms improved transiently and returned

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Case 2 Presentation

• On re-evaluation by PCP 11/4/02
• Worsened respiratory distress
• CXR revealed diffuse interstitial infiltrates
  ?pulmonary edema
• O2 SAT RA 86
• Admitted to Valdese General for further
  evaluation and management

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Case 2 Presentation

• Extensive work-up included
• r/o MI with serial cardiac enzymes, EKG
• TTE 11/5/02 nl LV fxn PASP 50mmHg
• CT-angiogram chest 11/5/02 alveolar edema and
  prominent paratracheal and subcarinal LAD no
  evidence of PE
• LE dopplers 11/5/02 (-) DVT
• Dobutamine sestamibi 11/6/02 (-) inducible
  ischemia
• PFTs mild obstruction

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Case 2 Presentation

• Received aggressive diuresis with some
  improvement in SOB
• On the evening of 11/8/02, became acutely more
  hypoxic
• ABG 7.42/30/38/19 78 on ??
• CXR worsening diffuse infiltrates
• Transferred to Valdese MICU and arrangements made
  for transfer to NCBH

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Case 2 Presentation

• On transfer 11/9/02, mild respiratory distress
  with 02 sats 90 on 40 FS
• ID consulted 11/10/02 for possible role of
  hepatitis C therapies, IFN and ribavirin, in
  development of acute lung injury

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CXR 11/10/02
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CT chest with and without contrast 11/11/02
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Case 2 Hospital Course

• Bronchoscopy deferred
• CT-guided biopsy of ?lung, paratracheal LN
  attempted 11/9/02?unrevealing
• Underwent bronch/BAL 11/14/02
• ? cell counts
• GS rare WBC, rare GPC, GNR
• Cx nl throat flora

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Case 2 Hospital Course

• Decision made to pursue open lung biopsy
• Biopsy performed 11/20/02

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Open Lung Biopsy

• GS 1 GPC CX 1 CNS
• Pathology all specimens show alterations ranging
  from minimally-affected, almost-normal thin
  septae to areas of dense fibrosis and
  honeycombing. Intermediate features include
  active fibrosis andchronic interstitial
  inflammation. This heterogenous pattern is best
  classified as USUAL INTERSTITIAL PNEUMONITIS

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Usual interstitial pneumonia (UIP)

• The "usual" pathological finding in patients with
  suspected idiopathic pulmonary fibrosis (IPF).
• Most cases sporadic and occur in patients who
  present in the 5th or 6th decade of life
  complaining of slowly progressive dyspnea and
  nonproductive cough.
• Men are affected more commonly than women by a
  ratio of nearly 21.
• Rare familial cases of IPF have been described.

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Usual interstitial pneumonia (UIP)

• Usually follows a relentlessly progressive
  course, with most patients dying of respiratory
  failure within 5 years of diagnosis.
• Periodic exacerbations associated with increased
  symptoms and an accelerated decline in pulmonary
  function are the rule and can be related to
  either variation in the tempo of the underlying
  lesion or superimposed complications of various
  types.

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Clinical conditions associated with UIP

• Idiopathic pulmonary fibrosis/cryptogenic
  fibrosing alveolitis
• Collagen vascular disease
• Drug toxicity
• Chronic hypersensitivity pneumonitis
• Asbestosis
• Familial IPF
• Hermansky-Pudlak syndrome

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Pulmonary Complications of Hepatitis C

• Hepatitis C virus-associated
• Therapy associated

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Extrahepatic manifestations of HCV Disease

• Lymphoproliferative disorders
• Mixed cryoglobulinemia
• Lymphoma
• Other extrahepatic diseases
• Autoimmune thyroiditis
• Sjogrens syndrome
• Idiopathic pulmonary fibrosis
• Dermatologic manifestations

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HCV and IPF

• Pathogenetic link between HCV infection and IPF
  has been suggested by
• findings of higher frequency of HCV markers in
  IPF patients than in normal controls
• observation that some patients with HCV-positive
  chronic hepatitis treated with IFN-alpha
  developed pulmonary fibrosis

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HCV and IPF

• Additionally, there was an increased count of
  lymphocytes and neutrophils in bronchoalveolar
  lavage fluid in patients with HCV chronic
  infection, suggesting that HCV infection may
  trigger alveolitis.
• However, there are conflicting epidemiological
  data, mainly from the UK, making this association
  an object of debate.

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HCV and IPF

• Mixed cryoglobulinemia may be complicated by
  interstitial lung involvement, suggesting the
  association between HCV and IPF may, in some
  cases, be indirect, and due to surrounding
  HCV-related mixed cryoglobulinemia.

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Pulmonary complications of alpha-interferon and
ribavirin

• Pulmonary complications of interferon are rare.
• Reported pulmonary complications include
  interstitial pneumonitis, pulmonary sarcoidosis,
  BOOP, pleural effusion, and exacerbation of
  bronchial asthma.

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Pulmonary complications of a-IFN and
ribavirinRibavirin

• Ribavirin is generally well-tolerated
• Pulmonary side effects such as cough and dyspnea
  are common side effects and may make detection of
  interferon associated lung injury more difficult

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Ribavirin Selected Treatment Adverse Events in
Untreated and Relapse Patients
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RIBAVIRIN

• Role of ribavirin in the development of pulmonary
  complications unclear
• In previous reports of interferon-related
  pulmonary toxicity other than sarcoidosis,
  interferon was the only agent used
• Could not find any published reports of serious
  pulmonary toxicity caused by ribavirin alone

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RIBAVIRIN

• Ribavirin may have independent pulmonary toxicity
  given the frequently associated symptoms of cough
  and dyspnea
• However,
• Ribavirin monotherapy is no longer used, and in
  patients on combination therapy it would be
  impossible to exclude interferon as a causative
  agent
• To date, rates of pulmonary toxicity with
  combination interferon/ribavirin seem no higher
  than with interferon alone

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a-interferon and pulmonary toxicity

• Asthma
• Sarcoidosis
• Interstitial lung disease
• BOOP
• Pleural effusions

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Kumar K, Russo M, Brown R et al. Significant
pulmonary toxicity associated with interferon and
ribavirin therapy for hepatitis C. Am Journal of
Gastroenterology. 2002 97(9) p.2432-2440.

• AIM to analyze the clinical presentation and
  outcomes of significant pulmonary toxicity
  associated with interferon and ribavirin.
• METHODS retrospective review of patients
  enrolled in four clinical trials at three sites,
  two academic medical centers and one community
  practice, and medical literature review.

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Kumar, Brown et al.

• Four cases of significant pulmonary toxicity were
  found or 5.7 of the patients enrolled in the
  three studies
• Three of the four were on more intensive
  interferon regimens with either daily dosing or
  pegylated interferon

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Kumar et al.Clinical Profile of the Four
Patients
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Kumar, Brown et al.

• Two of three patients on standard interferon
  received higher than conventional doses of
  interferon suggesting possible dose-dependent
  toxicity
• No relationship found to severity of liver
  disease or the presence or absence of virological
  response.

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Kumar, Brown et al.

• Incidence of pulmonary toxicity in high-dose
  studies 5.7 relatively high
• During that same time period, NO significant
  pulmonary toxicity was seen in the other 500
  HCV patients treated in the 3 practices.
• Thus, the overall incidence was lt1.

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Kumar, Brown et al.

• Whether the higher incidence in the high-dose
  studies reflected increased scrutiny and thus a
  detection bias or a truly increased incidence
  with higher doses of is not known.
• However, increased surveillance for adverse
  effects may be prudent in patients on high-dose
  interferon regimens or pegylated interferons.

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Pulmonary Toxicity of Interferon and
RibavirinConclusions

• Limited number of cases in the literature
  illustrate possible serious, but usually
  reversible, pulmonary toxicity associated with
  interferon therapy.
• Pulmonary toxicity is likely more common than
  previously believed because symptoms such as
  dyspnea or cough may be attributed to ribavirin
  and thus not investigated further with chest
  radiography.

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Pulmonary Toxicity of Interferon and
RibavirinConclusions

• Although respiratory symptoms are often observed
  with ribavirin, consider further investigation
  with pulmonary function tests, arterial blood
  gas, or chest x-ray, if symptoms are severe or
  persistent as they may reflect underlying
  pulmonary toxicity.

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Pulmonary Toxicity of Interferon and
RibavirinConclusions

• Kumar et al. obtained CXR in all patients with
  symptoms of cough or dyspnea that lasted greater
  than 2 wk and were severe enough to warrant
  consideration of discontinuation of therapy
  (510 of treated patients in their experience).
• Obtained further workup in patients with abnormal
  chest x-rays.

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Pulmonary Toxicity of Interferon and
RibavirinConclusions

• Though the definition of severity is somewhat
  subjective, this appears to be an adequate
  screening algorithm because all affected patients
  had abnormal x-rays , and no pulmonary toxicity
  has developed in the patients without
  radiographic changes.

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Pulmonary Toxicity of Interferon and
RibavirinConclusions

• As the precise mechanism of action of ribavirin
  in the treatment of hepatitis C is unclear, its
  role if any in causing pulmonary toxicity is
  unknown.

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Case 2

• Did receive high-dose corticosteroid therapy
  following open lung biopsy with minimal
  improvement
• Remained significantly hypoxic with 6-10L
  continuous O2 requirement
• D/C home with hospice support